Special Issue "Drug Metabolism/Transport and Pharmacokinetics"

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: 31 March 2020.

Special Issue Editor

Guest Editor
Prof. Dr. Im-Sook Song Website E-Mail
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
Interests: Pharmacokinetic drug-drug interaction; Pharmacokinetic herb-drug interaction; Drug metabolizing enzymes and transporters; Pharmacokinetic/Pharmacodynamics in drug development

Special Issue Information

Dear Colleagues,

Clinically important phase I and II metabolizing enzymes and transporters from two major superfamilies, ABC (ATP binding cassette) and SLC (Solute carrier) transporters, are designated and the pivotal roles of drug metabolizing enzymes and drug transporters in the pharmacokinetics, pharmacogenomics, and drug-drug interactions have been recognized. Therefore, researchers and regulatory agencies have made an effort to understand the pharmacokinetics, pharmacogenomics, and drug–drug interactions with respect to mechanistic changes in these drug metabolizing enzymes and transporters. With a trend of polypills and increased use of medicinal food, concurrent administration of herbal drugs can cause serious adverse reactions with substrate drugs of metabolizing enzymes and transporters by the potential for the inhibition or induction of their activities. For this, the prediction and evaluation of the contribution of drug metabolizing enzymes and transporters to the pharmacokinetics and drug–drug interaction potential of drugs or drug candidates are important in clinics and in the drug development process.

This Special Issue will highlight pharmacokinetics/drug–drug interactions and mechanistic understanding in relation to the drug metabolizing enzymes and drug transporters.

Prof. Dr. Im-Sook Song
Guest Editor

Manuscript Submission Information

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Keywords

  • pharmacokinetics
  • phase I and II metabolizing enzymes
  • drug transporters
  • drug–drug interaction
  • herb–drug interaction
  • enzyme inhibition and induction

Published Papers (3 papers)

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Research

Open AccessArticle
Pharmacokinetic Evaluation of Metabolic Drug Interactions between Repaglinide and Celecoxib by a Bioanalytical HPLC Method for Their Simultaneous Determination with Fluorescence Detection
Pharmaceutics 2019, 11(8), 382; https://doi.org/10.3390/pharmaceutics11080382 - 02 Aug 2019
Abstract
Since diabetes mellitus and osteoarthritis are highly prevalent diseases, combinations of antidiabetic agents like repaglinide (REP) and non-steroidal anti-inflammatory drugs (NSAID) like celecoxib (CEL) could be commonly used in clinical practice. In this study, a simple and sensitive bioanalytical HPLC method combined with [...] Read more.
Since diabetes mellitus and osteoarthritis are highly prevalent diseases, combinations of antidiabetic agents like repaglinide (REP) and non-steroidal anti-inflammatory drugs (NSAID) like celecoxib (CEL) could be commonly used in clinical practice. In this study, a simple and sensitive bioanalytical HPLC method combined with fluorescence detector (HPLC-FL) was developed and fully validated for simultaneous quantification of REP and CEL. A simple protein precipitation procedure and reversed C18 column with an isocratic mobile phase (mixture of ACN and pH 6.0 phosphate buffer) were employed for sample preparation and chromatographic separation. The fluorescence detector was set at a single excitation/emission wavelength pair of 240 nm/380 nm. The linearity (10–2000 ng/mL), accuracy, precision, extraction recovery, matrix effect, and stability for this method were validated as per the current FDA guidance. The bioanalytical method was applied to study pharmacokinetic interactions between REP and CEL in vivo, successfully showing that concurrent administration with oral REP significantly altered the pharmacokinetics of oral CEL. Furthermore, an in vitro metabolism and protein binding study using human materials highlighted the possibility of metabolism-based interactions between CEL and REP in clinical settings. Full article
(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics)
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Open AccessArticle
Identification of Catalposide Metabolites in Human Liver and Intestinal Preparations and Characterization of the Relevant Sulfotransferase, UDP-glucuronosyltransferase, and Carboxylesterase Enzymes
Pharmaceutics 2019, 11(7), 355; https://doi.org/10.3390/pharmaceutics11070355 - 22 Jul 2019
Abstract
Catalposide, an active component of Veronica species such as Catalpa ovata and Pseudolysimachion lingifolium, exhibits anti-inflammatory, antinociceptic, anti-oxidant, hepatoprotective, and cytostatic activities. We characterized the in vitro metabolic pathways of catalposide to predict its pharmacokinetics. Catalposide was metabolized to catalposide sulfate (M1), [...] Read more.
Catalposide, an active component of Veronica species such as Catalpa ovata and Pseudolysimachion lingifolium, exhibits anti-inflammatory, antinociceptic, anti-oxidant, hepatoprotective, and cytostatic activities. We characterized the in vitro metabolic pathways of catalposide to predict its pharmacokinetics. Catalposide was metabolized to catalposide sulfate (M1), 4-hydroxybenzoic acid (M2), 4-hydroxybenzoic acid glucuronide (M3), and catalposide glucuronide (M4) by human hepatocytes, liver S9 fractions, and intestinal microsomes. M1 formation from catalposide was catalyzed by sulfotransferases (SULTs) 1C4, SULT1A1*1, SULT1A1*2, and SULT1E1. Catalposide glucuronidation to M4 was catalyzed by gastrointestine-specific UDP-glucuronosyltransferases (UGTs) 1A8 and UGT1A10; M4 was not detected after incubation of catalposide with human liver preparations. Hydrolysis of catalposide to M2 was catalyzed by carboxylesterases (CESs) 1 and 2, and M2 was further metabolized to M3 by UGT1A6 and UGT1A9 enzymes. Catalposide was also metabolized in extrahepatic tissues; genetic polymorphisms of the carboxylesterase (CES), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for catalposide metabolism may cause inter-individual variability in terms of catalposide pharmacokinetics. Full article
(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics)
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Open AccessArticle
Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Intestinal First-Pass Metabolism
Pharmaceutics 2019, 11(7), 318; https://doi.org/10.3390/pharmaceutics11070318 - 05 Jul 2019
Abstract
This study investigated the pharmacokinetics of tofacitinib in rats and the effects of first-pass metabolism on tofacitinib pharmacokinetics. Intravenous administration of 5, 10, 20, and 50 mg/kg tofacitinib showed that the dose-normalized area under the plasma concentration-time curve from time zero to infinity [...] Read more.
This study investigated the pharmacokinetics of tofacitinib in rats and the effects of first-pass metabolism on tofacitinib pharmacokinetics. Intravenous administration of 5, 10, 20, and 50 mg/kg tofacitinib showed that the dose-normalized area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly higher at 50 mg/kg than at lower doses, a difference possibly due to saturation of the hepatic metabolism of tofacitinib. Oral administration of 10, 20, 50, and 100 mg/kg tofacitinib showed that the dose-normalized AUC was significantly higher at 100 mg/kg than at lower doses, a difference possibly due to saturation of the intestinal metabolism of tofacitinib. Following oral administration of 10 mg/kg tofacitinib, the unabsorbed fraction from the rat intestine was 3.16% and the bioavailability (F) was 29.1%. The AUC was significantly lower (49.3%) after intraduodenal, compared to intraportal, administration, but did not differ between intragastric and intraduodenal administration, suggesting that approximately 46.1% of orally administered tofacitinib was metabolized through an intestinal first-pass effect. The AUC was also significantly lower (42%) after intraportal, compared to intravenous, administration, suggesting that the hepatic first-pass effect on tofacitinib after entering the portal vein was approximately 21.3% of the oral dose. Taken together, these findings suggest that the low F of tofacitinib is due primarily to intestinal first-pass metabolism. Full article
(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics)
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