Cytochrome P450s of the 3A family (CYP3A) are perhaps the most clinically significant human drug metabolizing enzymes CYP3A4 is the most abundant hepatic and intestinal CYP. CYP3A5 metabolizes many, but not all, CYP3A4 substrates CYP3As metabolize >50% of all drugs, are a major determinant of first-pass (intestinal and hepatic) metabolism of oral drugs, and exhibit marked inter-individual variability due to diverse CYP3A4 expression, CYP3A5 genetic polymorphism and exquisite CYP3 A sensitivity to drug interactions. A major imperative has been the assessment of CYP3A activity, drug interactions, and resulting alterations in clinical drug effects. FDA regulations regarding new drug development require the identification of metabolizing enzyme(s) and clinical assessment of potential pharmacokinetic drug interactions. Myriad endeavors to identify and validate an ideal in vivo CYP3A probe 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 and implement a simple, sensitive, specific, inexpensive, and robust probe for the minimally or noninvasive assessment of CYP3A activity and drug interactions in humans. This investigation will test the hypothesis that the CYP3A opioid substrate alfentanil (ALF) can be used to minimally or non-invasively assess CYP3A activity. Specifically, that hepatic and first-pass CYP3A can be 1) simultaneously assessed in a single session and with a single minimal plasma sample using stable isotope ALF, and 2) individually assessed using pupil constriction (miosis) as a totally noninvasive surrogate for ALF plasma concentration and pharmacokinetics. That is, """"""""effect clearance"""""""" can replace plasma clearance, and thus ALF miosis is a noninvasive in vivo probe for CYP3A. Clinical studies in healthy volunteers and patients, using midazolam clearance as an independent measure of CYP3A, will evaluate relationships between ALF single-point concentration (minimally invasive probe), ALF effect clearance (noninvasive probe), ALF plasma clearance and CYP3A activity, for intravenous and oral ALF, to determine the: 1) validity of simultaneous hepatic and first-pass CYP3A single-point assessment, 2) probe sensitivity for detecting graded CYP3A induction, 3) influence of hepatic blood flow on the clearance of the CYP3A probes midazolam and ALF, and 4) ability of noninvasive ALF miosis to predict dose requirements for other CYP3A drugs. Successful validation and implementation of ALF will provide a novel technology for assessing CYP3A, the most important drug metabolism enzyme. This approach may identify inter-individual variability in drug disposition and response; permit more individualized dosing, and reduces the cost of drug interaction studies. ? ? ?
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