To search for the optimal dosage of phenytoin in patients with epilepsy based on the metabolic activities of CYP2C9 and CYP2C19 polymorphisms, a total of 169 patients receiving phenytoin treatment for more than 1 month were recruited. Phenytoin concentration, serum albumin, liver function tests, and renal function tests were measured. CYP2C9 and CYP2C19 polymorphisms were genotyped by PCR-RFLP analysis, and NONMEM models were built to evaluate factors that would affect phenytoin metabolism. Patients were divided into 5 groups according to genotyping results (G1 to G5). Compared with extensive metabolizers in both CYP2C9 and CYP2C19 (G1), the Vmax (mg/kg/d) was 8.29% and 36.96% lower in CYP2C19 poor metabolizers (G3) and CYP2C9 poor metabolizers (G4), respectively. For the patient who was identified as a poor metabolizer in both CYP2C19 and CYP2C9 (G5), the Vmax was 45.75% lower than that of G1. In respect to Km (mg/L), it was 15.09% higher in G3 and 27.36% higher in G4 compared with that in G1. The Km of G5 was 91.71% higher than that of G1. The results revealed that the CYP2C9 and CYP2C19 polymorphisms have dramatic effects on the population pharmacokinetic parameters of phenytoin, especially for CYP2C9. Based on the Vm and Km values obtained in this study, the recommended dose ranges for G1, G2, G3, G4, and G5 patients would be 5.5-7, 5-7, 5-6, 3-4, and 2-3 mg/kg/d, respectively.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1097/00007691-200410000-00012 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Potential Interaction of Pinocembrin with Drug Transporters and Hepatic Drug-Metabolizing Enzymes.
Pharmaceuticals (Basel)
January 2025
Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Ratchathewi, Bangkok 10400, Thailand.
: Pinocembrin is a promising drug candidate for treating ischemic stroke. The interaction of pinocembrin with drug transporters and drug-metabolizing enzymes is not fully revealed. The present study aims to evaluate the interaction potential of pinocembrin with cytochrome P450 (CYP450: CYP2B6, CYP2C9, and CYP2C19) and drug transporters including organic anion transporters (OAT1 and OAT3), organic cation transporters (OCT1 and OCT2), multidrug and toxin extrusion (MATE1 and MATE2, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP).
View Article and Find Full Text PDFThe metabolic pathway of Deg-AZM and investigations into the contribution of drug metabolizing enzymes and drug transporters in the drug interactions of Deg-AZM, a clinical-stage new transgelin agonist.
Front Pharmacol
January 2025
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
Introduction: Deglycosylated azithromycin (Deg-AZM), a new transgelin agonist with positive therapeutic effects on slow transit constipation, has been approved for clinical trials in 2024. This work investigated the drug metabolism and transport of Deg-AZM to provide research data for further development of Deg-AZM.
Methods: A combination of UPLC-QTOF-MS was used to obtain metabolite spectra of Deg-AZM in plasma, urine, feces and bile.
The refined CYP2B6-Template system for studies of its ligand metabolisms.
Drug Metab Pharmacokinet
November 2024
Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
The previously reported Template system for the prediction of human CYP2B6-mediated reactions (Drug Metab Pharmacokinet 26 309-330, 2011) has been refined with the introduction of ideas of allowable width, Trigger-residue and the residue-initiated movement of ligands in the active site. The refined system also includes ideas of bi-molecule binding on Template. With the use of these ideas in common with other Template systems for human CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, and CYP3A4, 360 reactions of 261 distinct chemicals reported as CYP2B6 ligands were examined in the refined system.
View Article and Find Full Text PDFHeterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol.
Pharmaceutics
December 2024
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
: Perillyl alcohol (POH), a monoterpene natural product derived from the essential oils of plants such as perilla (), is currently in phase I and II clinical trials as a chemotherapeutic agent. In this study, we investigated the effect of POH on cytochrome P450 (CYP) activity for evaluating POH-drug interaction potential. : The investigation was conducted using pooled human liver microsomes (HLMs), recombinant CYP3A4 (rCYP3A4) enzymes, and human pluripotent stem cell-derived hepatic organoids (hHOs) employing liquid chromatography-tandem mass spectrometry.
View Article and Find Full Text PDFPhysiologically based pharmacokinetic (PBPK) modeling of gliclazide for different genotypes of CYP2C9 and CYP2C19.
Arch Pharm Res
January 2025
College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea.
Article Synopsis
- Gliclazide is a medication for type 2 diabetes, primarily metabolized by genetic variations in the CYP2C9 and CYP2C19 enzymes.
- A physiologically based pharmacokinetic (PBPK) model was developed to analyze how these genetic differences affect gliclazide's effects in patients.
- The model accurately predicted drug concentration levels in the bloodstream, meeting standard evaluation criteria and potentially paving the way for personalized treatment plans based on genetic profiles.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!