PII‐17

BACKGROUND/AIMS Verapamil, a CYP3A4 substrate and inhibitor in vivo , is a more potent mechanistic inhibitor of CYP3A4 than CYP3A5 in vitro . We hypothesized that the clearance of verapamil would be different in subjects genetically capable of expressing CYP3A5 compared to non‐expressers. METHODS Twenty healthy subjects with predetermined CYP3A5 genotype were recruited. CYP3A5 *3, *6 and *7 genotypes were determined with real‐time PCR. After an outpatient course of verapamil 240 mg per day for 7 days, verapamil pharmacokinetics were determined on days 8 and 9. Serum concentrations of R‐ and S‐ verapamil and R‐ and S‐norverapamil were determined with by chiral LC/MS. Verapamil pharmacokinetics parameters were derived from non‐compartmental analysis (WinNonlin). Differences in the pharmacokinetic parameters among subjects with different CYP3A5 genotypes were tested with Student's t tests (SPSS v12). RESULTS CYP3A5 expressers (subjects with at least one *1 allele) had a statistically higher orally clearance for R and S verapamil ( table 1). There is a trend towards lower R‐ and S‐ verapamil Cmax in subjects who were CYP3A5 expressers. CYP3A5 genotype did not influence the R to S verapamil AUC ratio. Effect of CYP3A5 Expression on Verapamil PharmacokineticsExpressers (N=10) Non‐expressors (N=10) P ValueR‐verapamilCmax (ng/ml) 155.3 ± 28.7 282.5 ± 54.3 0.053 Cl/F (L/hour) 172.1 ± 27.8 94.3 ± 12.4 0.02 S‐verapamilCmax (ng/ml) 32.2 ± 6.9 67.2 ± 16.1 0.061 Cl/F (L/hour) 925.1 ± 162.7 473.7 ± 81.5 0.02 AUC ratioR/S Verapamil 5.3 ± 0.3 4.7 ± 0.3 0.21CONCLUSIONS CYP3A5 expressers may experience diminished pharmacological effect of verapamil due to a greater steady‐state oral clearance in this group. Clinical Pharmacology & Therapeutics (2005) 79 , P40–P40; doi: 10.1016/j.clpt.2005.12.142