A genetic test for immunosuppressant dose selection?

Department of Pharmaceutics, University of Washington, Seattle, Washington, USA Tel: +1 206 543 0819; fax: +1 206 543 3204; e-mail: [email protected] Correspondence and requests for reprints to Kenneth E. Thummel, Department of Pharmaceutics, University of Washington, Seattle, WA 98195-7610, USA. Identification of genetic mutations that affect the bioavailability, clearance and steady-state blood concentration of narrow therapeutic drugs has great potential for improving their safety and efficacy profile. Following the discovery of the genetic basis for polymorphic CYP3A5 expression in human hepatic and intestinal tissues [1–3], there has been intensive effort to establish whether this molecular phenomenon alters drug elimination in vivo in a clinically meaningful way. Because CYP3A4 is expressed in most if not all people, the effect of polymorphic CYP3A5 expression on the total metabolic clearance of CYP3A substrates is not readily predictable. Mutations in the CYP3A4 gene and large uncontrolled variability in non-genetic factors that perturb CYP3A function may confound the detection of a CYP3A5 genotype–clinical phenotype association.