Effect of the MDR1 C3435T variant and P-glycoprotein induction on dicloxacillin pharmacokinetics.
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 mug/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 +/- 7.0 microg/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.
Putnam
Wendy S
WS
Department of Biopharmaceutical Sciences, University of California, San Francisco, 513 Parnassus Avenue, Room U-68, San Francisco, CA 94143-0446, USA.
Woo
Jonathan M
JM
Huang
Yong
Y
Benet
Leslie Z
LZ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics*; D000328:Adult; D003596:Cytosine; D004009:Dicloxacillin / Q000493:pharmacokinetics*; D005260:Female; D019450:Genes, MDR / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013941:Thymine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003596:Cytosine; D004009:Dicloxacillin; D013941:Thymine