Influence of solute carriers on the pharmacokinetics of CYP3A4 probes.
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.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
R M
RM
Franke
S D
SD
Baker
R H
RH
Mathijssen
E G
EG
Schuetz
A
A
Sparreboom
D001944:Breath Tests; D051544:Cytochrome P-450 CYP3A / Q000187:drug effects / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004917:Erythromycin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D022781:Hepatocytes / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015336:Molecular Probe Techniques; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D029362:Organic Anion Transporters, Sodium-Independent / Q000187:drug effects / Q000235:genetics*; D010597:Pharmacogenetics; D012307:Risk Factors; D012680:Sensitivity and Specificity; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
D029362:Organic Anion Transporters, Sodium-Independent; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D004917:Erythromycin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam