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The Influence of CYP3A5 Genotype on Dexamethasone Induction of CYP3A Activity in African Americans

Division of Pharmacotherapy and Experimental Therapeutics (P.J.R., K.D.R., A.D.M.K., M.F.P., A.C.N., E.E.W., R.L.H.) and Department of Pediatrics, Division of Pediatric Hematology Oncology (C.M.), University of North Carolina, Chapel Hill, North Carolina; North Carolina Collaborative Pediatric Pharmacology Research Unit, Duke University Medical Center and University of North Carolina, Chapel Hill, North Carolina (C.M.); and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee (J.K.L., E.G.S.)

The CYP3A5^*1 allele has been associated with differences in the metabolism of some CYP3A substrates. CYP3A5 polymorphism may also influence susceptibility for certain drug interactions. We have previously noted a correlation between basal CYP3A activity and the inductive effects of dexamethasone using the erythromycin breath test (ERBT). To determine whether CYP3A5 polymorphism influences induction of CYP3A activity, we examined the effect of an antiemetic regimen of dexamethasone, and the prototypical inducer rifampin, on the ERBT in African American volunteers prospectively stratified by CYP3A5^*1 allele carrier status. Mean basal ERBTs were significantly higher in CYP3A5^*1 carriers (2.71 ± 0.53%) versus noncarriers (2.12 ± 0.37%, P = 0.006). Rifampin increased ERBTs in CYP3A5^*1 carriers (4.68 versus 2.60%, P = 0.0008) and noncarriers (3.55 versus 2.11%, P = 0.0017), whereas dexamethasone increased ERBTs only in CYP3A5^*1 noncarriers (3.03 versus 2.14%, P = 0.031). CYP3A5 polymorphism appears to influence susceptibility to induction-type drug interactions for some inducers, and CYP3A5^*1 noncarriers may be more susceptible to the inductive effects of dexamethasone as a result of lower basal CYP3A activity.