Influence of solute carriers on the pharmacokinetics of CYP3A4 probes.

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Franke RM, Baker SD, Mathijssen RH, Schuetz EG, Sparreboom A

Influence of solute carriers on the pharmacokinetics of CYP3A4 probes.

Clin Pharmacol Ther. 2008 Dec;84(6):704-9. doi: 10.1038/clpt.2008.94. Epub 2008 May 28.

PubMed ID

18509328 [ View in PubMed

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Abstract

We hypothesized that the assessment of baseline CYP3A4 activity is influenced by probe-specific differences in hepatocellular uptake mechanisms. There was no significant correlation between the erythromycin breath test (ERMBT) parameters and midazolam clearance in 30 cancer patients (R(2) < 0.01), regardless of their CYP3A5 genotype status. In cellular models overexpressing 10 different solute carriers, erythromycin uptake was significantly increased by OATP1A2 (P < 0.005) and OATP1B3 (P < 0.01). Midazolam was not a substrate for any of the tested transporters. In a separate cohort of 119 patients, 6 nonsynonymous variants in the OATP1B3 gene SLCO1B3 were identified. Individuals carrying two copies of the T allele at the 334 locus had a 2.4-fold lower value for ERMBT 1/T(max) (P = 0.001), a measure reflecting more rapid hepatic uptake. These findings suggest that differential affinities for solute carriers should be considered when selecting an appropriate phenotypic probe to allow tailored dosing of pharmaceuticals that are CYP3A4 substrates.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Erythromycin	Solute carrier organic anion transporter family member 1A2	Protein	Humans	Unknown	Substrate Inhibitor	Details
Erythromycin	Solute carrier organic anion transporter family member 1B1	Protein	Humans	No	Substrate Inhibitor	Details
Erythromycin	Solute carrier organic anion transporter family member 1B3	Protein	Humans	Unknown	Substrate Inhibitor	Details