Effect of the <i>MDR1</i> C3435T Variant and P‐Glycoprotein Induction on Dicloxacillin Pharmacokinetics
抄録
<jats:p>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<jats:sub><jats:italic>max</jats:italic></jats:sub> 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<jats:sub><jats:italic>max</jats:italic></jats:sub> 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 ± 0.77 h (P 7< .05). Rifampin treatment increased the formation clearance, C<jats:sub><jats:italic>max</jats:italic></jats:sub>, 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.</jats:p>
収録刊行物
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- The Journal of Clinical Pharmacology
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The Journal of Clinical Pharmacology 45 (4), 411-421, 2005-04
Wiley
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詳細情報 詳細情報について
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- CRID
- 1362262943635130752
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- NII論文ID
- 30007804760
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- ISSN
- 15524604
- 00912700
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- データソース種別
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