Novel noninvasive assessment of cytochrome P450 activity

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Cytochrome P450s of the 3Afamily are perhaps the most clinically significant enzymes in human drug metabolism. P4503A4 (CYP3A4) is the most quantitatively abundant hepatic and intestinal CYP. CYP3A5 metabolized numerous, but not all, CYP3A4 substrates. CYP3A enzymes are responsible for the hepatic metabolism of greater than 50 percent of all drugs, and are increasingly recognized as a major determinant of first-pass metabolism (intestinal and hepatic) of oral drugs. CYP3A activity exhibits marked interindividual variability, owing to broad levels of CYP3A4 expression, genetic polymorphism in CYP3A4 expression, and exquisite CYP3A sensitivity to drug interactions. A major imperative has been the determination of drug influence on CYP3A4 activity, drug interactions, and, resulting alterations in clinical drug effects. Indeed, FDA regulations regarding new drug development require the identification of metabolizing enzyme(s), assessment of potential clinical pharmacokinetic drug interactions, and preferably, their pharmacodynamic consequences. Myriad endeavors to identify and validate an ideal in vivo metabolic probe for CYP3A4/5 have, unfortunately, not succeeded. All current CYP3A probes have known limitations, require some invasiveness, and are based on plasma or urine pharmacokinetics. The goal of this research program is to develop a sensitive, specific, noninvasive, inexpensive, robust, simple, and utilitarian probe for assessing CYP3A activity and CYP3A drug interaction in humans, primarily CYP3A4, and secondarily CYP3A5. This investigation will test the hypothesis that pupil constriction (miosis) caused by the CYP3A4-selective opioid alfentanil (ALF) can be used as a surrogate plasma concentration and pharmacokinetic measure, and thus as a noninvasive probe for in vivo CYP3A4 activity. That is, "effect clearance" can replace plasma clearance. A series of clinical investigations, using midazolam clearance as an independent measure of CYP3A4 activity, and genotypic CYP3A5 analysis, will evaluate the relationship between ALF effect clearance ("the probe"), ALF plasma clearance, and CYP3A4 activity, as well as between ALF and midazolam clearances, for intravenous and oral ALF in 1) subjects with deliberately altered intestinal and hepatic CYP3A activity to validate the probe, 2) a broad population to assess interindividual reliability of the probe, 3) repetitively studied subjects to assess interindividual repeatability of the probe, and 4) subjects with specific degrees of deliberately reduced CYP3A activity, to assess the sensitivity of the probe. Successful validation of ALF effect clearance may provide a novel technology for assessing CYP3A, the most important drug metabolism enzyme in humans. Such technology may identify mechanisms of interindividual variability in drug disposition and response, permit more individualized dosing, and reduce the cost of drug interaction studies by an order of magnitude or more.