Prediction of Drug Interactions With CYP2C9 Substrates

Condition(s) targeted: Healthy Volunteers

Intervention: Phenytoin (Drug); Rifampicin (Drug); Diclophenac (Drug); Fluconazole (Drug)

Phase: N/A

Status: Completed

Sponsored by: Hadassah Medical Organization

Official(s) and/or principal investigator(s):
Yoseph Caraco, MD, Principal Investigator, Affiliation: Hadassah Medical Organization

CYP2C9, is one of the major drug metabolism enzymes accounting for about 20% of the hepatic cytochrome P450 content and being second only to CYP3A4.

The proposed study will explore different possible drug interactions with CYP2C9 substrates by evaluating the effect of prototype inducers and inhibitors on the phenotypic trait measurement. It is expected that the identification of drugs that might interact with CYP2C9 substrates will be used to rationalize future drug interaction studies designed to evaluate the actual magnitude of effect and its clinical implications. This approach should be particularly useful when applied to those CYP2C9 drugs characterized by a narrow therapeutic index (i. e. warfarin).

This study will consist of three study periods separated from each other by a two weeks washout period. In the course of the study the subjects will receive in a double blind, crossover fashion, rifampin 300 mg. twice daily, diclofenac 50 mg twice daily. and fluconazole 200 mg. twice daily, each for one week. All drugs will be administered as identical looking tablets that will be prepared at the pharmacy of the Hadassah University Hospital and their order of administration will be randomized. On the day prior to, on day 6 of and 7 days following each drug period, the activity of CYP2C9 will be evaluated by the administration of a single phenytoin 300 mg. dose. The subjects will be requested to collect their urine for 24 hours and a single blood sample will be obtained 12 hours post phenytoin intake.

Official title: Prediction of Potential Drug Interaction With CYP2C9 Substrate by Using Phenytoin Metabolic Ratio as a Marker of Its Activity in-Vivo.

Study design: Other, Randomized, Double-Blind, Active Control, Crossover Assignment, Pharmacokinetics Study

Primary outcome: Phenytoin metabolic ratio prior to and following exposure to fluconazole, diclophenac and rifampicin.

Minimum age: 20 Years. Maximum age: 50 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Age range 20-50

- Absence of significant disease states

Exclusion Criteria:

- Known hypersensitivity to one of the drugs used in the study

- Significant disease states

- Regular use of drugs (including birth control pills)

Hadassah Medical Organization, Jerusalem, Israel

Starting date: August 1999
Last updated: March 17, 2008