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Effect of the MDR1 C3435T Variant and P-Glycoprotein Induction on Dicloxacillin Pharmacokinetics

From the Department of Biopharmaceutical Sciences, School of Pharmacy (Dr Putnam, Dr Benet); Genomics Core Facility, Department of Biochemistry and Biophysics (Mr Woo); and Drug Studies Unit, School of Pharmacy (Dr Huang), University of California, San Francisco.

This study investigated 2 hypotheses about genotype-phenotype relationships for the efflux transporter, P-glycoprotein: (1) the presence of a synonymous C3435T variant in exon 26 of the MDR1 gene correlates to higher plasma concentrations of a P-glycoprotein substrate, dicloxacillin, and (2) the effects of genotypic differences decrease under conditions of P-glycoprotein induction by rifampin. Eighteen healthy volunteers received two 1-g doses of dicloxacillin, one on the 1st study day and the other on the 11th day of rifampin dosing (600 mg daily). Dicloxacillin and its 5-hydroxymethyl metabolite were analyzed using liquid chromatography/tandem mass spectrometry. Mean dicloxacillin C_max measurements were 30.5 ± 13.5, 33.3 ± 4.7, and 31.1 ± 12.8 µg/mL in individuals with the CC, CT, and TT genotype at position 3435 in exon 26 of the MDR1 gene. Following rifampin dosing, the mean dicloxacillin C_max across genotypes decreased from 31.4 ± 10.8 to 22.9 ± 7.0µg/mL (P < .05), whereas the mean oral clearance increased from 235 ± 82 to 297 ± 71 mL/min (P < .001), and the mean absorption time increased from 0.71 ± 0.55 to 1.34 ± 0.77 h (P < .05). Rifampin treatment increased the formation clearance, C_max, and AUC of the 5-hydroxymethyl metabolite by 135%, 119%, and 59%, respectively. The C3435T variant had no effect on dicloxacillin pharmacokinetics. The data suggested that rifampin induced intestinal P-glycoprotein and increased dicloxacillin metabolism.

Key Words: MDR1 variant • P-glycoprotein • dicloxacillin • pharmacokinetics

Address for reprints: Leslie Z. Benet, PhD, Department of Biopharmaceutical Sciences, University of California, San Francisco, 513 Parnassus Avenue, Room U-68, San Francisco, CA 94143-0446.

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