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


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Abstract

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 Cmaxmeasurements 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 Cmax across genotypes decreased from 31.4 ± 10.8 to 22.9 ± 7.0 μg/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 ± 0.77h (P < .05). Rifampin treatment increased the formation clearance, Cmax, 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.

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