Time-dependent inhibition of CYP3A4-mediated midazolam metabolism by macrolide antibiotics in CYP3A4 genetic variants: Comparison with testosterone metabolism

International journal of clinical pharmacology and therapeutics

Published On 2021/12

Objectives The present study aimed to evaluate the effects of CYP3A4 genetic variation on the kinetics of mechanism-based inhibition (MBI) of both inhibitors using midazolam as a substrate for comparison with our previous study, as midazolam and testosterone have different binding sites. Background The genetic variation of cytochrome P450 (CYP) 3A4 affects MBI, expressed as the maximum inactivation rate constant (k inact, max) and the inhibitor concentration required to achieve half-maximal inactivation (K I). We previously showed, using testosterone as a substrate, that the MBI kinetics of erythromycin and clarithromycin differ among CYP3A4 variants. Materials and methods Midazolam 1’-hydroxylation inactivation profiles of erythromycin and clarithromycin were assessed using recombinant CYP3A4. 1,. 2,. 7,. 16, and. 18 expressed in Escherichia coli. MBI parameters were calculated from changes in the …

Journal

International journal of clinical pharmacology and therapeutics

Published On

2021/12

Volume

59

Issue

12

Page

745

Authors

Fred Guengerich

Fred Guengerich

Vanderbilt University

Position

Professor of Biochemistry

H-Index(all)

175

H-Index(since 2020)

51

I-10 Index(all)

0

I-10 Index(since 2020)

0

Citation(all)

0

Citation(since 2020)

0

Cited By

0

Research Interests

Enzymology

drug metabolism

cytochrome P450

mutagenesis

University Profile Page

Mitsue Miyazaki

Mitsue Miyazaki

University of California, San Diego

Position

H-Index(all)

36

H-Index(since 2020)

18

I-10 Index(all)

0

I-10 Index(since 2020)

0

Citation(all)

0

Citation(since 2020)

0

Cited By

0

Research Interests

MRI

Other Articles from authors

Mitsue Miyazaki

Mitsue Miyazaki

University of California, San Diego

Magnetic resonance imaging apparatus and magnetic resonance imaging method

A magnetic resonance imaging apparatus includes sequence controlling circuitry and processing circuitry. The sequence controlling circuitry executes (i) a first pulse sequence in which a spatially selective Inversion recovery (IR) pulse and a spatially non-selective IR pulse are applied, and (ii) a second pulse sequence in which the spatially non-selective IR pulse is applied without applying the spatially selective IR pulse, while varying the first TI period, with respect to a plurality of first TI periods. The sequence controlling circuitry executes (iii) the third pulse sequence in which the spatially selective IR pulse and the spatially non-selective IR pulse are applied, and (iv) the fourth pulse sequence in which the spatially non-selective IR pulse is applied without applying the spatially selective IR pulse. The processing circuitry generates a magnetic resonance image of an imaged region based on data obtained from the …

Mitsue Miyazaki

Mitsue Miyazaki

University of California, San Diego

Magnetic Resonance in Medical Sciences

Aliphatic and Olefinic Fat Suppression in the Orbit Using Polarity-altered Spectral and Spatial Selective Acquisition (PASTA) with Opposed Phase

Purpose: Fatty acid composition of the orbit makes it challenging to achieve complete fat suppression during orbit MR imaging. Implementation of a fat suppression technique capable of suppressing signals from saturated (aliphatic) and unsaturated (olefinic or protons at double-bonded carbon sites) fat would improve the visualization of an optical nerve. Furthermore, the ability to semi-quantify the fractions of aliphatic and olefinic fat may potentially provide valuable information in assessing orbit pathology.Methods: A phantom study was conducted on various oil samples on a clinical 3 Tesla scanner. The imaging protocol included three 2D fast spin echo (FSE) sequences: in-phase, polarity-altered spectral and spatial selective acquisition (PASTA), and a combination of PASTA with opposed phase in olefinic and aliphatic chemical shift. The results were validated against high-resolution 11.7 T NMR and compared with images acquired with spectral attenuated inversion recovery (SPAIR) and chemical shift selective (CHESS) fat suppression techniques. In-vivo data were acquired on eight healthy subjects and were compared with the prior histological studies.Results: PASTA with opposed phase achieved complete suppression of fat signals in the orbits and provided images of well-delineated optical nerves and muscles in all subjects. The olefinic fat fraction in the olive, walnut, and fish oil phantoms at 3T was found to be 5.0%, 11.2%, and 12.8%, respectively, whereas 11.7 T NMR provides the following olefinic fat fractions: 6.0% for olive, 11.5% for walnut, and 12.6% for fish oils. For the in-vivo study, on average, olefinic fat accounted for 9.9%±3.8 …

Mitsue Miyazaki

Mitsue Miyazaki

University of California, San Diego

Magnetic Resonance in Medical Sciences

Physical exercise alters egress pathways for intrinsic CSF outflow: an investigation performed with spin-labeling MR imaging

Purpose: Cerebrospinal fluid (CSF) clearance is essential for maintaining a healthy brain and cognition by removal of metabolic waste from the central nervous system. Physical exercise has been shown to improve human health; however, the effect of physical exercise on intrinsic CSF outflow in humans remains unexplored. The purpose of this study was to investigate intrinsic CSF outflow pathways and quantitative metrics of healthy individuals with active and sedentary lifestyles. In addition, the effect of exercise was investigated among the sedentary subjects before and after 3 weeks of physical activity.Methods: This study was performed on 18 healthy adults with informed consent, using a clinical 3-Tesla MRI scanner. We classified participants into two groups based on reported time spent sitting per day (active group:< 7 hours sitting per day and sedentary group:≥ 7 hours sitting per day). To elucidate the effect of exercise, sedentary individuals increased their activity to 3.5 hours for 3 weeks.Results: We show that there are two intrinsic CSF egress pathways of the dura mater and lower parasagittal dura (PSD). The adults with an active lifestyle had greater intrinsic CSF outflow metrics than adults with a more sedentary lifestyle. However, after increased physical activity, the sedentary group showed improved CSF outflow metrics. This improvement was particularly notable at the lower PSD, where outflow metrics were highest among the active group.Conclusion: Our findings describe the relationship between physical activity and intrinsic CSF outflow and show a potential selective outflow pathway with increasing physical activity in the lower …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Medicinal Chemistry

Identification of Potent and Selective Inhibitors of Acanthamoeba: Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Fat mass obesity-associated protein (FTO) is a DNA/RNA demethylase involved in the epigenetic regulation of various genes and is considered a therapeutic target for obesity, cancer, and neurological disorders. Here, we aimed to design novel FTO-selective inhibitors by merging fragments of previously reported FTO inhibitors. Among the synthesized analogues, compound 11b, which merges key fragments of Hz (3) and MA (4), inhibited FTO selectively over alkylation repair homologue 5 (ALKBH5), another DNA/RNA demethylase. Treatment of acute monocytic leukemia NOMO-1 cells with a prodrug of 11b decreased the viability of acute monocytic leukemia cells, increased the level of the FTO substrate N6-methyladenosine in mRNA, and induced upregulation of MYC and downregulation of RARA, which are FTO target genes. Thus, Hz (3)/MA (4) hybrid analogues represent an entry into a new class of FTO …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Chemical Research in Toxicology

In Vivo and In Vitro Induction of Cytochrome P450 3A4 by Thalidomide in Humanized-Liver Mice and Experimental Human Hepatocyte HepaSH cells

Autoinduction of cytochrome P450 (P450) 3A4-mediated metabolism of thalidomide was investigated in humanized-liver mice and human hepatocyte-derived HepaSH cells. The mean plasma ratios of 5-hydroxythalidomide and glutathione adducts to thalidomide were significantly induced (3.5- and 6.0-fold, respectively) by thalidomide treatment daily at 1000 mg/kg for 3 days and measured at 2 h after the fourth administration (on day 4). 5-Hydroxythalidomide was metabolically activated by P450 3A4 in HepaSH cells pretreated with 300 and 1000 μM thalidomide, and 5,6-dihydroxythalidomide was detected. Significant induction of P450 3A4 mRNA expression (4.1-fold) in the livers of thalidomide-treated mice occurred. Thalidomide exerts a variety of actions through multiple mechanisms following bioactivation by induced human P450 3A enzymes.

Fred Guengerich

Fred Guengerich

Vanderbilt University

Formation of potentially toxic metabolites of drugs in reactions catalyzed by human drug-metabolizing enzymes

Data are presented on the formation of potentially toxic metabolites of drugs that are substrates of human drug metabolizing enzymes. The tabular data lists the formation of potentially toxic/reactive products. The data were obtained from in vitro experiments and showed that the oxidative reactions predominate (with 96% of the total potential toxication reactions). Reductive reactions (e.g., reduction of nitro to amino group and reductive dehalogenation) participate to the extent of 4%. Of the enzymes, cytochrome P450 (P450, CYP) enzymes catalyzed 72% of the reactions, myeloperoxidase (MPO) 7%, flavin-containing monooxygenase (FMO) 3%, aldehyde oxidase (AOX) 4%, sulfotransferase (SULT) 5%, and a group of minor participating enzymes to the extent of 9%. Within the P450 Superfamily, P450 Subfamily 3A (P450 3A4 and 3A5) participates to the extent of 27% and the Subfamily 2C (P450 2C9 and P450 2C19 …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

Proteomics, modeling, and fluorescence assays delineate cytochrome b5 residues involved in binding and stimulation of cytochrome P450 17A1 17, 20-lyase

Cytochrome b5 (b5) is known to stimulate some catalytic activities of cytochrome P450 (P450, CYP) enzymes, although mechanisms still need to be defined. The reactions most strongly enhanced by b5 are the 17,20-lyase reactions of P450 17A1 involved in steroid biosynthesis. We had previously used a fluorescently labeled human b5 variant (Alexa 488-T70C-b5) to characterize human P450 17A1-b5 interactions, but subsequent proteomic analyses indicated that lysines in b5 were also modified with Alexa 488 maleimide in addition to Cys-70, due to disulfide dimerization of the T70C mutant. A series of b5 variants were constructed with Cys replacements for the identified lysine residues and labeled with the dye. Fluorescence attenuation and the function of b5 in the steroid lyase reaction depended on the modified position. Apo-b5 (devoid of heme group) studies revealed the lack of involvement of the b5 heme in …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Angewandte Chemie

Oxygen‐18 Labeling Reveals a Mixed Fe− O Mechanism in the Last Step of Cytochrome P450 51 Sterol 14α‐Demethylation

The 14α‐demethylation step is critical in eukaryotic sterol biosynthesis, catalyzed by cytochrome P450 (P450) Family 51 enzymes, for example, with lanosterol in mammals. This conserved three‐step reaction terminates in a C−C cleavage step that generates formic acid, the nature of which has been controversial. Proposed mechanisms involve roles of P450 Compound 0 (ferric peroxide anion, FeO2−) or Compound I (perferryl oxygen, FeO3+) reacting with either the aldehyde or its hydrate, respectively. Analysis of 18O incorporation into formic acid from 18O2 provides a means of distinguishing the two mechanisms. Human P450 51A1 incorporated 88 % 18O (one atom) into formic acid, consistent with a major but not exclusive FeO2− mechanism. Two P450 51 orthologs from amoeba and yeast showed similar results, while two orthologs from pathogenic trypanosomes showed roughly equal contributions of both …

Mitsue Miyazaki

Mitsue Miyazaki

University of California, San Diego

Magnetic Resonance in Medical Sciences

Age-related decline of intrinsic cerebrospinal fluid outflow in healthy humans detected with non-contrast spin-labeling MR imaging

PurposeClearance of cerebrospinal fluid (CSF) is important for the removal of toxins from the brain, with implications for neurodegenerative diseases. Imaging evaluation of CSF outflow in humans has been limited, relying on venous or invasive intrathecal injections of contrast agents. The objective of this study was to introduce a novel spin-labeling MRI technique to detect and quantify the movement of endogenously tagged CSF, and then apply it to evaluate CSF outflow in normal humans of varying ages.MethodsThis study was performed on a clinical 3-Tesla MRI scanner in 16 healthy subjects with an age range of 19–71 years with informed consent. Our spin-labeling MRI technique applies a tag pulse on the brain hemisphere, and images the outflow of the tagged CSF into the superior sagittal sinus (SSS). We obtained 3D images in real time, which was analyzed to determine tagged-signal changes in different …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

Ninety-eight semesters of cytochrome P450 enzymes and related topics—What have I taught and learned?

This Reflection article begins with my family background and traces my career through elementary and high school, followed by time at the University of Illinois, Vanderbilt University, the University of Michigan, and then for 98 semesters as a Vanderbilt University faculty member. My research career has dealt with aspects of cytochrome P450 enzymes, and the basic biochemistry has had applications in fields as diverse as drug metabolism, toxicology, medicinal chemistry, pharmacogenetics, biological engineering, and bioremediation. I am grateful for the opportunity to work with the Journal of Biological Chemistry not only as an author but also for 34 years as an Editorial Board Member, Associate Editor, Deputy Editor, and interim Editor-in-Chief. Thanks are extended to my family and my mentors, particularly Profs. Harry Broquist and Minor J. Coon, and the more than 170 people who have trained with me. I have …

Fred Guengerich

Fred Guengerich

Vanderbilt University

ACS catalysis

Oxygen-18 Labeling Defines a Ferric Peroxide (Compound 0) Mechanism in the Oxidative Deformylation of Aldehydes by Cytochrome P450 2B4

Most cytochrome P450 (P450) oxidations are considered to occur with the active oxidant being a perferryl oxygen (FeO3+, Compound I). However, a ferric peroxide (FeO2̅, Compound 0) mechanism has been proposed, as well, particularly for aldehyde substrates. We investigated three of these systems, the oxidative deformylation of the model substrates citronellal, 2-phenylpropionaldehyde, and 2-methyl-2-phenylpropionaldehyde by rabbit P450 2B4, using 18O labeling. The formic acid product contained one 18O derived from 18O2, which is indicative of a dominant Compound 0 mechanism. The formic acid also contained only one 18O derived from H218O, which ruled out a Compound I mechanism. The possibility of a Baeyer–Villiger reaction was examined by using synthesized possible intermediates, but our data do not support its presence. Overall, these findings unambiguously demonstrate the role of the …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Principles of Xenobiotic Metabolism (Biotransformation)

This chapter provides a general overview of metabolic reactions and their significance. Basic concepts and terminology related to biotransformation, activity, and toxicityToxicity are explained and discussed. Major enzymes involved in oxidationOxidation, reductionReduction, hydrolytic, and conjugationConjugation are covered including enzyme nomenclature, localization, catalytic cycle, coenzymes, relevance of individual enzymes, types of reactions, substrates and metabolites, influence of metabolic reactions on the activity/toxicity of xenobiotics, enzyme inhibition, and relevance if applicable.

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

The multistep oxidation of cholesterol to pregnenolone by human cytochrome P450 11A1 is highly processive

Cytochrome P450 (P450, CYP) 11A1 is the classical cholesterol side chain cleavage enzyme (P450scc) that removes six carbons of the side chain, the first and rate-limiting step in the synthesis of all mammalian steroids. The reaction is a 3-step, 6-electron oxidation that proceeds via formation of 22R-hydroxy (OH) and 20R,22R-(OH)2 cholesterol, yielding pregnenolone. We expressed human P450 11A1 in bacteria, purified the enzyme in the absence of nonionic detergents, and assayed pregnenolone formation by HPLC-mass spectrometry of the dansyl hydrazone. The reaction was inhibited by the nonionic detergent Tween 20, and several lipids did not enhance enzymatic activity. The 22R-OH and 20R,22R-(OH)2 cholesterol intermediates were bound to P450 11A1 relatively tightly, as judged by steady-state optical titrations and koff rates. The electron donor adrenodoxin had little effect on binding; the substrate …

2023/11/24

Article Details
Mitsue Miyazaki

Mitsue Miyazaki

University of California, San Diego

Japanese Journal of Radiology

Non-contrast MRI of micro-vascularity of the feet and toes

PurposeThis study aimed to develop novel non-contrast MR perfusion techniques for assessing micro-vascularity of the foot in human subjects.MethodsAll experiments were performed on a clinical 3 T scanner using arterial spin labeling (ASL). Seven healthy subjects (30–72 years old, 5 males and 2 females) were enrolled and bilateral feet were imaged with tag-on and tag-off alternating inversion recovery spin labeling for determining micro-vascularity. We compared an ASL technique with 1-tag against 4-tag pulses. For perfusion, we determined signal increase ratio (SIR) at varying inversion times (TI) from 0.5 to 2 s. SIR versus TI data were fit to determine perfusion metrics of peak height (PH), time to peak (TTP), full width at half maximum (FWHM), area under the curve (AUC), and apparent blood flow (aBF) in the distal foot and individual toes. Using analysis of variance (ANOVA), effects of tag pulse and region of …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Journal of Biological Chemistry

Processive kinetics in the three-step lanosterol 14α-demethylation reaction catalyzed by human cytochrome P450 51A1

Cytochrome P450 (P450, CYP) family 51 enzymes catalyze the 14α-demethylation of sterols, leading to critical products used for membranes and the production of steroids, as well as signaling molecules. In mammals, P450 51 catalyzes the 3-step, 6-electron oxidation of lanosterol to form (4β,5α)-4,4-dimethyl-cholestra-8,14,24-trien-3-ol (FF-MAS). P450 51A1 can also use 24,25-dihydrolanosterol (a natural substrate in the Kandutsch-Russell cholesterol pathway). 24,25-Dihydrolanosterol and the corresponding P450 51A1 reaction intermediates, the 14α-alcohol and -aldehyde derivatives of dihydrolanosterol, were synthesized to study the kinetic processivity of the overall 14α-demethylation reaction of human P450 51A1. A combination of steady-state kinetic parameters, steady-state binding constants, dissociation rates of P450-sterol complexes, and kinetic modeling of the time course of oxidation of a P450 …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Nucleic Acids Research

Basis for the discrimination of supercoil handedness during DNA cleavage by human and bacterial type II topoisomerases

To perform double-stranded DNA passage, type II topoisomerases generate a covalent enzyme-cleaved DNA complex (i.e. cleavage complex). Although this complex is a requisite enzyme intermediate, it is also intrinsically dangerous to genomic stability. Consequently, cleavage complexes are the targets for several clinically relevant anticancer and antibacterial drugs. Human topoisomerase IIα and IIβ and bacterial gyrase maintain higher levels of cleavage complexes with negatively supercoiled over positively supercoiled DNA substrates. Conversely, bacterial topoisomerase IV is less able to distinguish DNA supercoil handedness. Despite the importance of supercoil geometry to the activities of type II topoisomerases, the basis for supercoil handedness recognition during DNA cleavage has not been characterized. Based on the results of benchtop and rapid-quench flow kinetics experiments, the forward …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Xenobiotica

The influence of temperature on the metabolic activity of CYP2C9, CYP2C19, and CYP3A4 genetic variants in vitro

1. Temperature is considered to affect the activity of drug-metabolizing enzymes; however, no previous studies have compared temperature dependency among cytochrome P450 genetic variants. This study aimed to analyse warfarin 7-hydroxylation by CYP2C9 variants; omeprazole 5-hydroxylation by CYP2C19 variants; and midazolam 1-hydroxylation by CYP3A4 variants at 34 °C, 37 °C, and 40 °C.2. Compared with that seen at 37 °C, the intrinsic clearance rates (Vmax/Km) of CYP2C9.1 and .2 were decreased (76 ∼ 82%), while that of CYP2C9.3 was unchanged at 34 °C. At 40 °C, CYP2C9.1, .2, and .3 exhibited increased (121%), unchanged and decreased (87%) intrinsic clearance rates, respectively. At 34 °C, the clearance rates of CYP2C19.1A and .10 were decreased (71 ∼ 86%), that of CYP2C19.1B was unchanged, and those of CYP2C19.8 and .23 were increased (130 ∼ 134%). At 40 …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Food and Chemical Toxicology

FEMA GRAS assessment of natural flavor complexes: Lemongrass oil, chamomile oils, citronella oil and related flavoring ingredients

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, eleventh in the series, evaluates the safety of NFCs characterized by primary alcohol, aldehyde, carboxylic acid, ester and lactone constituents derived from terpenoid biosynthetic pathways and/or lipid metabolism. The scientific-based evaluation procedure published in 2005 and updated in 2018 that relies on a complete constituent characterization of the NFC and organization of the constituents into congeneric groups. The safety of the NFCs is evaluated using the threshold of toxicological concern (TTC) concept in addition to data on estimated intake, metabolism and toxicology of members of the congeneric groups and for the NFC under evaluation. The scope of the safety evaluation …

Fred Guengerich

Fred Guengerich

Vanderbilt University

Food and Chemical Toxicology

FEMA GRAS assessment of derivatives of basil, nutmeg, parsley, tarragon and related allylalkoxybenzene-containing natural flavor complexes

In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavoring ingredients in food. In this publication, tenth in the series, NFCs containing a high percentage of at least one naturally occurring allylalkoxybenzene constituent with a suspected concern for genotoxicity and/or carcinogenicity are evaluated. In a related paper, ninth in the series, NFCs containing anethole and/or eugenol and relatively low percentages of these allylalkoxybenzenes are evaluated. The Panel applies the threshold of toxicological concern (TTC) concept and evaluates relevant toxicology data on the NFCs and their respective constituent congeneric groups. For NFCs containing allylalkoxybenzene constituent(s), the estimated intake of the constituent is compared to the TTC for compounds with structural …

Mitsue Miyazaki

Mitsue Miyazaki

University of California, San Diego

Japanese Journal of Radiology

3D T1rho sequences with FASE, UTE, and MAPSS acquisitions for knee evaluation

PurposeFor biochemical evaluation of soft tissues of the knee, T1rho magnetic resonance imaging (MRI) has been proposed. Purpose of this study was to compare three T1rho sequences based on fast advanced spin echo (FASE), ultrashort echo time (UTE), and magnetization-prepared angle-modulated partitioned k-space spoiled gradient echo snapshots (MAPSS) acquisitions for the knee evaluation.Materials and methodsWe developed two T1rho sequences using 3D FASE or 3D radial UTE acquisitions. 3D MAPSS T1rho was provided by the manufacturer. Agarose phantoms with varying concentrations were imaged. Additionally, bilateral knees of asymptomatic subjects were imaged sagittally. T1rho values of the phantoms and 4 regions of interest (ROI) of the knees (i.e., anterior and posterior meniscus, femoral and tibial cartilage) were determined.ResultsIn phantoms, all T1rho values monotonically …

Other articles from International journal of clinical pharmacology and therapeutics journal

Min-Gul Kim

Min-Gul Kim

Chonbuk National University

International Journal of Clinical Pharmacology and Therapeutics

Pharmacokinetics and bioequivalence of tofacitinib 5 mg in healthy Korean male subjects.

ObjectiveTofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz).Materials and methodsA randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (C max) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC 0-t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for C max and AUC 0-t were calculated to evaluate pharmacokinetic equivalence.ResultsThe 90% CIs of the geometric mean ratios of C max and AUC 0-t for tofacitinib free base to tofacitinib citrate were 0.9144-1.1230 and 1.0245-1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events.ConclusionIn healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent …

Walaa Alsanie

Walaa Alsanie

Taif University

International Journal of Clinical Pharmacology and Therapeutics

Therapeutic drug monitoring of vancomycin in surgical patients through a validated HPLC method.

BackgroundVancomycin is being used for the treatment of a variety of infections caused by methicillin resistant Staphylococcus aureus and methicillin susceptible Staphylococcus aureus. Therapeutic drug monitoring (TDM) is highly recommended for ensuring the safe and effective therapy with vancomycin. A reliable and cost-effective bioanalytical method is required for TDM as well as pharmacokinetic studies of vancomycin.Materials and methodsA selective, sensitive, and cost effective HPLC method was developed and validated for quantification of vancomycin concentrations in human plasma. The mobile phase was a mixture of buffer (50 mM ammonium dihydrogen phosphate, pH 2.4) and acetonitrile 88: 12 v/v. The separation was carried on C18 column (125× 4.6 mm, particle size 5 µm) with isocratic flow rate of 0.370 mL/min at room temperature with UV detection at 215 nm. The method was validated for sensitivity, accuracy, and precision as well as stability of vancomycin in human plasma by following European Medicine Agency (EMA) guideline. Therapeutic drug monitoring of vancomycin was performed by quantifying the trough concentrations of vancomycin in 65 human plasma samples after administration of therapeutically relevant dose.ResultsThe developed method was sensitive enough to quantify vancomycin concentrations as low as 0.25 mg/L in human plasma. Moreover, the method was proved accurate and precise in terms of quantifying the unknown concentration of vancomycin. The evaluation of short-term, long-term, and freeze-thaw stability proved the stability of vancomycin in human plasma. The TDM of vancomycin by …

Majid alhomrani

Majid alhomrani

Taif University

International Journal of Clinical Pharmacology and Therapeutics

Therapeutic drug monitoring of vancomycin in surgical patients through a validated HPLC method.

BackgroundVancomycin is being used for the treatment of a variety of infections caused by methicillin resistant Staphylococcus aureus and methicillin susceptible Staphylococcus aureus. Therapeutic drug monitoring (TDM) is highly recommended for ensuring the safe and effective therapy with vancomycin. A reliable and cost-effective bioanalytical method is required for TDM as well as pharmacokinetic studies of vancomycin.Materials and methodsA selective, sensitive, and cost effective HPLC method was developed and validated for quantification of vancomycin concentrations in human plasma. The mobile phase was a mixture of buffer (50 mM ammonium dihydrogen phosphate, pH 2.4) and acetonitrile 88: 12 v/v. The separation was carried on C18 column (125× 4.6 mm, particle size 5 µm) with isocratic flow rate of 0.370 mL/min at room temperature with UV detection at 215 nm. The method was validated for sensitivity, accuracy, and precision as well as stability of vancomycin in human plasma by following European Medicine Agency (EMA) guideline. Therapeutic drug monitoring of vancomycin was performed by quantifying the trough concentrations of vancomycin in 65 human plasma samples after administration of therapeutically relevant dose.ResultsThe developed method was sensitive enough to quantify vancomycin concentrations as low as 0.25 mg/L in human plasma. Moreover, the method was proved accurate and precise in terms of quantifying the unknown concentration of vancomycin. The evaluation of short-term, long-term, and freeze-thaw stability proved the stability of vancomycin in human plasma. The TDM of vancomycin by …

Jinqi Fan

Jinqi Fan

Emory & Henry College

International Journal of Clinical Pharmacology and Therapeutics

Efficacy and safety of antiplatelet therapy in COVID-19: Insights from a meta-analysis of randomized controlled trials.

BackgroundCOVID-19 induces a pro-coagulant state with thrombotic events. This meta-analysis explores the efficacy and safety of antiplatelet-based therapy in COVID-19 patients through randomized controlled trials (RCTs).Materials and methodsA systematic literature search until March 10, 2023, identified 7 RCTs involving 23,415 inpatients. Of these, 11,891 received antiplatelet-based treatment, and 11,524 received placebo/other drugs. Statistical analysis was performed using Review Manager 5.4.ResultsThe included trials involved patients with a mean age ranging from 54.3 to 62.0 years and a prevalence of hypertension ranging from 10.9 to 65.0% and coronary artery disease ranging from 3.2 to 32.7%. The pooled analysis showed no significant difference in overall mortality between groups (RR 1.0, 95% CI 0.99-1.01, p= 0.76). However, antiplatelet therapy significantly reduced major thrombotic events (RR 0.86, 95% CI 0.75-0.99, p= 0.04). Conversely, it increased major bleeding risks (RR 1.62, 95% CI 1.24-2.12, p= 0.0005). There was no significant difference in the incidence of invasive mechanical ventilation and respiratory death.ConclusionAntiplatelet therapy does not confer mortality benefit in COVID-19 patients but lowers major thrombotic events while increasing major bleeding risks. Ongoing large RCTs will provide more information on the therapeutic value of this therapy.

Dr. Abdulhakeem Alamri

Dr. Abdulhakeem Alamri

Taif University

International Journal of Clinical Pharmacology and Therapeutics

Therapeutic drug monitoring of vancomycin in surgical patients through a validated HPLC method.

BackgroundVancomycin is being used for the treatment of a variety of infections caused by methicillin resistant Staphylococcus aureus and methicillin susceptible Staphylococcus aureus. Therapeutic drug monitoring (TDM) is highly recommended for ensuring the safe and effective therapy with vancomycin. A reliable and cost-effective bioanalytical method is required for TDM as well as pharmacokinetic studies of vancomycin.Materials and methodsA selective, sensitive, and cost effective HPLC method was developed and validated for quantification of vancomycin concentrations in human plasma. The mobile phase was a mixture of buffer (50 mM ammonium dihydrogen phosphate, pH 2.4) and acetonitrile 88: 12 v/v. The separation was carried on C18 column (125× 4.6 mm, particle size 5 µm) with isocratic flow rate of 0.370 mL/min at room temperature with UV detection at 215 nm. The method was validated for sensitivity, accuracy, and precision as well as stability of vancomycin in human plasma by following European Medicine Agency (EMA) guideline. Therapeutic drug monitoring of vancomycin was performed by quantifying the trough concentrations of vancomycin in 65 human plasma samples after administration of therapeutically relevant dose.ResultsThe developed method was sensitive enough to quantify vancomycin concentrations as low as 0.25 mg/L in human plasma. Moreover, the method was proved accurate and precise in terms of quantifying the unknown concentration of vancomycin. The evaluation of short-term, long-term, and freeze-thaw stability proved the stability of vancomycin in human plasma. The TDM of vancomycin by …

Abdulsamet Erden

Abdulsamet Erden

Hacettepe Üniversitesi

International journal of clinical pharmacology and therapeutics

Calcineurin inhibitors experience in unplanned pregnancies with active lupus disease: A retrospective observational study.

ObjectivesTo evaluate the use of calcineurin inhibitors (CNIs), specifically tacrolimus, in unplanned pregnancies with active lupus disease among patients with systemic lupus erythematosus (SLE).Materials and methodsThe study includes data from pregnancies in women diagnosed with SLE at Gazi University Hospital in Ankara, Türkiye, between January 2010 and July 2022. The study categorized pregnancies into planned and unplanned groups based on lupus nephritis presence, emphasizing the need for inactive lupus disease for at least 6 months before attempting conception in planned pregnancies. The outcomes of pregnancies involving CNIs, particularly tacrolimus, were assessed.ResultsIn our cohort comprising 632 SLE patients, 39 individuals reported 42 pregnancies. Among the 42 pregnancies, 14 have a history of lupus nephritis. We observed that 8 of 14 patients with a history of lupus nephritis had unplanned pregnancies. Three patients used cyclosporine and 2 used tacrolimus during their pregnancy; their pregnancies were completely healthy, and no lupus flare was observed during their pregnancies. The pregnancy of 2 patients who used azathioprine and 1 last patient who used no immunosuppressive treatment ended in abortion.ConclusionThis study reveals that tacrolimus can be effectively used in unplanned pregnancies with active lupus disease, providing favorable maternal and fetal outcomes. The findings emphasize the importance of considering CNIs, particularly tacrolimus, in the management of SLE pregnancies, even in cases of unplanned pregnancies with a history of lupus nephritis.

Chen Zhou

Chen Zhou

University of Massachusetts Medical School

International Journal of Clinical Pharmacology and Therapeutics

Application of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy

Objective: To evaluate the adverse effects and particularly the anesthetic effect of low-dose etomidate combined with oxycodone and midazolam in endoscopic injection sclerotherapy.Materials and methods: We herein report a prospective, double-blind, randomized controlled trial. It included patients with liver cirrhosis (age, 18–65 years; BMI, 18–25 kg/m2) who were treated with endoscopic injection sclerotherapy, and the patients were randomly assigned to the propofol group or the etomidate group. The incidence of respiratory depression was the primary outcome measure. The occurrence of various adverse effects and endoscopist satisfaction score were the secondary outcome measures.Results: In this study, we enrolled a total of 96 patients. The incidence of respiratory depression in the propofol group was 19%, while that in the etomidate group was only 4%(9/47 vs. 2/49; p= 0.026). Regarding the secondary …

Min-Gul Kim

Min-Gul Kim

Chonbuk National University

International Journal of Clinical Pharmacology and Therapeutics

Comparative pharmacokinetics of two formulations of 2.5-mg rivaroxaban in healthy Korean subjects.

ObjectiveRivaroxaban is a direct factor Xa inhibitor used for the prevention and treatment of thromboembolic disorders. The objective of this study was to compare the pharmacokinetic profiles of two rivaroxaban formulations after a single dose of rivaroxaban (2.5-mg tablet) in healthy Korean subjects.Materials and methodsThis study was a randomized, open-label, single-dose, two-period, crossover study that included 34 healthy adult subjects under fasting conditions. The test drug (Yuhan rivaroxaban tablet) or reference drug (Xarelto tablet) was administered in each period. Serial blood samples were collected up to 36 hours post-dose. Plasma concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) for the ratio of the geometric means of C max and AUC t for the test drug/reference drug were calculated to evaluate pharmacokinetic equivalence.ResultsA total of 28 subjects were included in the pharmacokinetic analysis. The geometric mean ratios (90% CI) of the test drug/reference drug for rivaroxaban were 1.0140 (0.9794-1.0499) for AUC t and 0.9350 (0.8797-0.9939) for C max. All adverse events (AEs) were mild, and there was no significant difference in the incidence of AEs between the formulations.ConclusionThe pharmacokinetic parameters of rivaroxaban were compared between the test and reference drug, and both formulations were bioequivalent. The newly …

Mahdi Alamri

Mahdi Alamri

King Faisal University

International Journal of Clinical Pharmacology and Therapeutics

Prevalence and risk factors of non-adherence to antipsychotic medications in Saudi Arabia

Purpose: To evaluate the rate and determinants of non-adherence to antipsychotic medications in Saudi Arabia.Materials and methods: This was a cross-sectional study that included a questionnaire, interview, and data extraction from medical records of adult patients on antipsychotic medications. The study was conducted at outpatient clinics at the psychological care department at King Fahad Medical City, Riyadh, Saudi Arabia, between October 25 and November 26, 2020. Data collection included three parts: patients’ sociodemographic characteristics; antipsychotic medications used and patients’ clinical characteristics; and adherence to antipsychotic medications measured by the Medication Adherence Rating Scale (MARS).Results: Out of 220 patients, 122 (55.5%) were considered non-adherent (MARS scores 6 or less). The MARS items contributing most to non-adherence were “the medication makes me …

Mary F Paine

Mary F Paine

Washington State University

International Journal of Clinical Pharmacology and Therapeutics

Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in …

Objective Fexofenadine is a probe drug used to phenotype P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 activities. This study evaluated a limited sampling strategy using plasma concentrations and/or partial area under the concentration versus time curves (AUCs) to estimate systemic exposure and, potentially, P-gp and OATP1B1/3 activities. Materials and methods Plasma concentration versus time data were obtained from 53 healthy adult participants (22 females) from four published studies. Participants were administered a single oral dose (120 mg) of fexofenadine during constitutive P-gp and OATP1B1/3 conditions. Concentration-time data were divided into a training (n= 18) and validation (n= 35) set. Backwards stepwise linear regression generated single-, 2-timepoint, and partial AUC limited sampling models (LSMs). Noncompartmental analysis methods were used to …

karel allegaert

karel allegaert

Katholieke Universiteit Leuven

International journal of clinical pharmacology and therapeutics

Neonatal pain score after use of paracetamol: Is there a relationship with serum trough concentration at steady state in preterm and term neonates?

ObjectiveAn easy to establish and patient-friendly biomarker to guide dosing of paracetamol in neonates is currently not available. The aim of this study was to determine the potential association between the serum trough concentration and area under the curve (AUC) of paracetamol at steady state and differences in pain scores in preterm and term neonates.Materials and methodsA retrospective observational study was performed, using an academic hospital database to identify neonates treated with intravenous or rectal paracetamol for at least 48 hours. At steady state, serum trough concentrations and the 24-hour AUC were determined. Pain was measured by COMFORTneo scores, before the 1st and 6th dose. Linear regression was performed to assess the association between serum trough concentration and 24-hour AUC and differences in pain scores. Subgroup analyses were performed for patients who received paracetamol due to a COMFORTneo score≥ 14 (group 1) or who received prophylactic paracetamol because of upcoming surgery (group 2).Results21 neonates were included. The median (interquartile range (IQR)) serum trough concentration of paracetamol before the 6th dose was 4.5 mg/L (2.7-8.5 mg/L). In subgroup 1, the median (IQR) COMFORTneo scores before the 1st and 6th dose were 17 (16.5-20) and 12 (11-16.5), respectively. In subgroup 2, the median (IQR) scores were 9 (8-10) and 11 (9-12), respectively. The serum trough concentration and 24-hour AUC were not associated with reduced pain scores (p= 0.12 and p= 0.67, respectively).ConclusionNo association was found between the serum trough …

Nidhi

Nidhi

Hamdard University

International Journal of Clinical Pharmacology and Therapeutics

Metformin alone and in combination with sitagliptin induces depression and impairs quality of life in type 2 diabetes mellitus patients: An observational study

Background: Various studies have reported the association of cognition and depression with diabetes. Literature suggests that metformin and sitagliptin used to control hyperglycemia in type 2 diabetes mellitus (T2DM) possess a beneficial effect on neurological symptoms associated with diabetes. However, there are scarce data in the clinical setting. Thus, this study aims to compare depression, cognitive impairment, and quality of life (QoL) of newly diagnosed T2DM patients with those of healthy individuals. Further, the impact of metformin alone or in combination with dipeptidyl peptidase-4 inhibitors on cognition, depression, and QoL of T2DM patients was also compared with newly diagnosed T2DM patients.Materials and methods: This was a prospective observational study in 120 subjects. The subjects were equally divided into four groups: healthy controls, newly diagnosed T2DM patients, and T2DM patients …

Thomas D. Nolin, PharmD, PhD

Thomas D. Nolin, PharmD, PhD

University of Pittsburgh

International Journal of Clinical Pharmacology and Therapeutics

Limitations of fexofenadine limited sampling strategy using plasma concentrations and partial area under the concentration-time curve to estimate transporter activity in …

Objective Fexofenadine is a probe drug used to phenotype P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 activities. This study evaluated a limited sampling strategy using plasma concentrations and/or partial area under the concentration versus time curves (AUCs) to estimate systemic exposure and, potentially, P-gp and OATP1B1/3 activities. Materials and methods Plasma concentration versus time data were obtained from 53 healthy adult participants (22 females) from four published studies. Participants were administered a single oral dose (120 mg) of fexofenadine during constitutive P-gp and OATP1B1/3 conditions. Concentration-time data were divided into a training (n= 18) and validation (n= 35) set. Backwards stepwise linear regression generated single-, 2-timepoint, and partial AUC limited sampling models (LSMs). Noncompartmental analysis methods were used to …

Karen Manuelyan

Karen Manuelyan

Trakia University

International Journal of Clinical Pharmacology and Therapeutics

Gliptin-induced bullous pemphigoid.

ObjectivesBullous pemphigoid (BP) is a rare, autoimmune, blistering disease in elderly patients that can be triggered by external factors including drugs. Drug-induced bullous pemphigoid (DIBP) does not always follow a self-limiting course after the withdrawal of the offending drug. Dipeptidyl peptidase-4 (DPP-4) inhibitors or gliptins seem to be associated with a significant risk of inducing BP.

2023/11/30

Article Details
Sunil Kohli

Sunil Kohli

Jamia Hamdard

International Journal of Clinical Pharmacology and Therapeutics

Metformin alone and in combination with sitagliptin induces depression and impairs quality of life in type 2 diabetes mellitus patients: An observational study

Background: Various studies have reported the association of cognition and depression with diabetes. Literature suggests that metformin and sitagliptin used to control hyperglycemia in type 2 diabetes mellitus (T2DM) possess a beneficial effect on neurological symptoms associated with diabetes. However, there are scarce data in the clinical setting. Thus, this study aims to compare depression, cognitive impairment, and quality of life (QoL) of newly diagnosed T2DM patients with those of healthy individuals. Further, the impact of metformin alone or in combination with dipeptidyl peptidase-4 inhibitors on cognition, depression, and QoL of T2DM patients was also compared with newly diagnosed T2DM patients.Materials and methods: This was a prospective observational study in 120 subjects. The subjects were equally divided into four groups: healthy controls, newly diagnosed T2DM patients, and T2DM patients …

Divya Vohora

Divya Vohora

Jamia Hamdard

International Journal of Clinical Pharmacology and Therapeutics

Metformin alone and in combination with sitagliptin induces depression and impairs quality of life in type 2 diabetes mellitus patients: An observational study

Background: Various studies have reported the association of cognition and depression with diabetes. Literature suggests that metformin and sitagliptin used to control hyperglycemia in type 2 diabetes mellitus (T2DM) possess a beneficial effect on neurological symptoms associated with diabetes. However, there are scarce data in the clinical setting. Thus, this study aims to compare depression, cognitive impairment, and quality of life (QoL) of newly diagnosed T2DM patients with those of healthy individuals. Further, the impact of metformin alone or in combination with dipeptidyl peptidase-4 inhibitors on cognition, depression, and QoL of T2DM patients was also compared with newly diagnosed T2DM patients.Materials and methods: This was a prospective observational study in 120 subjects. The subjects were equally divided into four groups: healthy controls, newly diagnosed T2DM patients, and T2DM patients …

Dr. Mohd ashif Khan

Dr. Mohd ashif Khan

Jamia Hamdard

International Journal of Clinical Pharmacology and Therapeutics

Metformin alone and in combination with sitagliptin induces depression and impairs quality of life in type 2 diabetes mellitus patients: An observational study

Background: Various studies have reported the association of cognition and depression with diabetes. Literature suggests that metformin and sitagliptin used to control hyperglycemia in type 2 diabetes mellitus (T2DM) possess a beneficial effect on neurological symptoms associated with diabetes. However, there are scarce data in the clinical setting. Thus, this study aims to compare depression, cognitive impairment, and quality of life (QoL) of newly diagnosed T2DM patients with those of healthy individuals. Further, the impact of metformin alone or in combination with dipeptidyl peptidase-4 inhibitors on cognition, depression, and QoL of T2DM patients was also compared with newly diagnosed T2DM patients.Materials and methods: This was a prospective observational study in 120 subjects. The subjects were equally divided into four groups: healthy controls, newly diagnosed T2DM patients, and T2DM patients …

Khalid K Abdul-Razzak

Khalid K Abdul-Razzak

Jordan University of Science and Technology

International Journal of Clinical Pharmacology and Therapeutics

Self-reported urinary urgency in association with vitamin D and psychiatric symptoms among patients with musculoskeletal pain.

ObjectivesUrinary urgency (UU) is linked to musculoskeletal pain (MSP), and it is associated with mental health conditions. This study examined the prevalence of UU morbidity among outpatients with MSP, and the possible association of UU with psychological symptoms and vitamin D deficiency.Materials and methodsA cross-sectional study was conducted among 169 participants recruited from outpatient clinics at King Abdullah University Hospital in Jordan. Participants completed self-guided questionnaires that included information about MSP and UU. Psychological symptoms were evaluated using the Hospital Anxiety and Depression Scale (HADS). A blood sample was collected for measuring vitamin D levels. Regression analysis was performed to explore predictors of MSP and UU.ResultsVitamin D deficiency was presented in 64.5% of participants, while UU was reported among 35.4% of MSP patients. Approximately 1/3 of participants had psychiatric symptoms (HADS≥ 8). Regression analyses revealed a significant association between vitamin D deficiency, low calcium intake, and anxiety scores with MSP (p< 0.05), while anxiety score was a significant predictor of UU among MSP patients (adjusted OR= 4.26, p= 0.038). A moderately significant correlation between anxiety score and frequency of UU per day was also observed (r= 0.303, p= 0.041).ConclusionUrinary urgency was prevalent among MSP patients and was strongly associated with anxiety symptoms. The findings suggest the importance of assessment of MSP patients for UU and the associated psychological symptoms so interventions may be potentially implemented to …

Abdulsamet Erden

Abdulsamet Erden

Hacettepe Üniversitesi

International Journal of Clinical Pharmacology and Therapeutics

Is compressed colchicine tablet superior to other colchicine preparations in patients with familial Mediterranean fever?

The aim of our study is to evaluate the differences in effectiveness, dosage, and side effect profiles in the use of colchicine preparations and evaluate the superiority of compressed colchicine tablets in familial Mediterranean fever (FMF) patients with resistance or intolerance to coated colchicine tablets. Patients who were diagnosed with FMF according to the Tel Hashomer criteria, aged 18 years and older, and switched from compressed colchicine to coated colchicine tablets in the rheumatology clinic of Gazi University were identified. The daily colchicine dose and FMF attack frequency before and after switching from coated colchicine tablets to compressed colchicine tablets were compared. The study included 43 female (72.9%) and 16 male patients (27.1%), and the mean age was 34.54±8.3 years. The number of attacks per year was significantly reduced after switching to compressed colchicine tablets, and daily colchicine doses were lower after switching to compressed colchicine tablets (1.97±0.23 vs 1.78±0.39 mg, p< 0.001). Compressed colchicine tablets were shown to be superior to other colchicine preparations and compressed colchicine tablets to be a useful treatment option before initiating biological agents in patients who were unresponsive to coated colchicine.

2023/11/16

Article Details
Simon Davies

Simon Davies

University of Toronto

International Journal of Clinical Pharmacology and Therapeutics

Novel intranasal treatment for anxiety disorders using amiloride, an acid-sensing ion channel antagonist: Pharmacokinetic modeling and simulation

Objective To develop a physiologically based pharmacokinetic (PBPK) model for amiloride, an acid-sensing ion channel (ASIC) antagonist, and to simulate its pharmacokinetics in plasma and the central nervous system following intranasal administration in a virtual human population. Materials and methods We first developed a PBPK model of amiloride after oral administration and optimized the model using data from 5 clinical studies. Next, we added a nasal compartment to the amiloride oral PBPK model and parameterized using data from previous clinical studies. We simulated amiloride’s pharmacokinetics in plasma, brain, and cerebrospinal fluid (CSF) after intranasal administration of amiloride at various doses in a virtual human population. Results The target amiloride concentration in the central nervous system required for maximal ASIC inhibition was achieved with a 75-mg intranasal amiloride dose. However, this finding is based on simulations performed using a mathematical model and needs to be further validated with appropri-citation