Background: Phenytoin, a cytochrome P450 (CYP) 2C9 substrate, has a narrow therapeutic index and nonlinear pharmacokinetics. Therefore there is the potential for significant concentration-related adverse effects when phenytoin is coadministered with other CYP2C9 substrates. Losartan, an antihypertensive agent, is also a substrate for CYP2C9.
Objective: Our objective was to assess the effects of losartan on the pharmacokinetics of phenytoin and the effects of phenytoin on the pharmacokinetics of losartan in a healthy population of volunteers.
Methods: A prospective, randomized, 3-period crossover study was conducted in 16 healthy volunteers with phenytoin alone, phenytoin in combination with losartan, and losartan alone. Each treatment was given for 10 days with a 3-week washout period between treatments. On day 10, plasma concentrations of phenytoin and plasma and urine concentrations of losartan and its active carboxylic-acid metabolite E3174 were measured to determine steady-state pharmacokinetic parameters.
Results: Coadministration of losartan had no effect on the pharmacokinetics of phenytoin. Coadministration of phenytoin increased the mean area under the concentration-time curve from time zero to 24 hours [AUC(0-24)] of losartan by 17% (355 +/- 220 ng x h/mL versus 427 +/- 177 ng x h/mL; P =.1), but this difference was not statistically significant. In the 14 CYP2C9*1/*1 subjects, the mean AUC(0-24) of losartan was increased by 29% (284 +/- 84 ng x h/mL versus 402 +/- 128 ng x h/mL; P =.008). Coadministration of phenytoin significantly reduced the AUC(0-24) of E3174 by 63% (1254 +/- 256 ng x h/mL versus 466 +/- 174 ng x h/mL; P =.0001) and the formation clearance of losartan to E3174 (1.91 +/- 0.8 mL/h per kilogram versus 0.62 +/- 0.4 mL/h per kilogram; P =.0001).
Conclusions: Losartan, a CYP2C9 substrate, had no effect on the pharmacokinetics of phenytoin. However, phenytoin inhibited the CYP2C9-mediated conversion of losartan to E3174.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1067/mcp.2002.127945 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Design, synthesis and structure-activity relationship of novel 1,2,4-triazolopyrimidin-5-one derivatives targeting GABA and Na1.2 with antiepileptic activity.
Eur J Med Chem
January 2025
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xiannongtan Street, Xicheng district, Beijing, 100050, China. Electronic address:
A novel class of 7-phenyl-[1,2,4]triazol-5(4H)-one derivatives was designed and synthesized, and their in vivo anticonvulsant activities were evaluated using subcutaneous pentylenetetrazole (Sc-PTZ) and maximal electroshock (MES) tests. Compounds 3u, 4f and 4k exhibited significant anticonvulsant activities in the Sc-PTZ model with ED values of 23.7, 17.
View Article and Find Full Text PDFValproic acid-induced hyperammonemia with encephalopathy in adults: A meta-analysis.
Int J Clin Pharmacol Ther
January 2025
Objective: Valproic acid, frequently prescribed for neurological and psychiatric disorders, can cause hyperammonemia (HA). This retrospective study aimed to investigate the association among the basic characteristics, comorbidities, co-medications, and risk of HA in patients receiving valproic acid.
Materials And Methods: We compared groups with and without HA using data collected from the medical records of adults undergoing valproic acid monitoring between January 1, 2019, and December 31, 2021.
Prediction of Pharmacoresistance in Drug-Naïve Temporal Lobe Epilepsy Using Ictal EEGs Based on Convolutional Neural Network.
Neurosci Bull
January 2025
Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, College of Pharmaceutical Sciences, The Second Affiliated Hospital of Zhejiang Chinese Medical University (Xinhua Hospital), Zhejiang Chinese Medical University, Hangzhou, 310053, China.
Approximately 30%-40% of epilepsy patients do not respond well to adequate anti-seizure medications (ASMs), a condition known as pharmacoresistant epilepsy. The management of pharmacoresistant epilepsy remains an intractable issue in the clinic. Its early prediction is important for prevention and diagnosis.
View Article and Find Full Text PDFSimultaneous determination of busulfan, fludarabine, phenytoin, and posaconazole in plasma from patients undergoing hematopoietic stem cell transplantation.
J Pharm Biomed Anal
January 2025
Department of Pharmacy, Hebei Children's Hospital, Shijiazhuang, Hebei 050031, China. Electronic address:
A simple, fast, sample-saving, and sensitive liquid chromatography-tandem mass spectrometry method was established with a linear range adjusted by in-source collision-induced dissociation. Notably, this could simultaneously determine busulfan, fludarabine, phenytoin, and posaconazole in plasma from children, each having unique physical and chemical properties. The procedure necessitated only 20 μL of plasma and involved a simple protein precipitation process.
View Article and Find Full Text PDFDrug-Induced Myoclonus: A Systematic Review.
Medicina (Kaunas)
January 2025
Neurology Department, Cooper University Hospital, Camden, NJ 08103, USA.
: Myoclonus is already associated with a wide variety of drugs and systemic conditions. As new components are discovered, more drugs are suspected of causing this disabling abnormal involuntary movement. This systematic review aims to assess the medications associated with drug-induced myoclonus (DIM).
View Article and Find Full Text PDFWant 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!