CYP3A5 genotype has a dose-dependent effect on ABT-773 plasma levels

• Published in: Clinical pharmacology and therapeutics Vol. 75; no. 6; p. 516
• Main Authors: Katz, David A, Grimm, David R, Cassar, Steven C, Gentile, Maria C, Ye, Xin, Rieser, Matthew J, Gordon, Eric F, Polzin, Jill E, Gustavson, Linda E, Driscoll, Rita M, O'dea, Robert F, Williams, Laura A, Bukofzer, Stanley
• Format: Journal Article
• Language: English
• Published: United States 01.06.2004
• Subjects: Adolescent; Adult; Aged; Area Under Curve; Confidence Intervals; Cross-Over Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; Dose-Response Relationship, Drug; Double-Blind Method; Erythromycin - administration & dosage; Erythromycin - analogs & derivatives; Erythromycin - blood; Erythromycin - chemistry; Female; Genes, MDR - genetics; Genotype; Humans; Ketolides; Male; Middle Aged; Statistics, Nonparametric
• DOI: 10.1016/j.clpt.2004.01.013
• ISSN: 0009-9236

The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically expressed as a result of genetic variants that do not encode functional protein. Because of overlapping substrate specificity with CYP3A4 and the multidrug efflux pump P-glycoprotein, the importance of CYP3A5 genetic polymorphism for pharmacokinetics is controversial. Our objective was to determine whether genetic polymorphisms in CYP3A5 or MDR-1 (which encodes P-glycoprotein) influence the drug levels of ABT-773, a ketolide antibiotic that is a substrate for both CYP3A and P-glycoprotein. Healthy volunteers given 3 different oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1 polymorphisms. Individuals were categorized as CYP3A5-positive if they carried at least 1 functional CYP3A5*1 allele and as CYP3A5-negative if they did not. Area under the plasma concentration-time curves (AUCs) from 0 to 6 hours (AUC(t)) and maximum postdose plasma concentration (C(max)) after a single dose and on day 5 of a twice-daily regimen were calculated and correlated with genotypes. ABT-773 AUC(t) and C(max) were, on average, higher in CYP3A5-negative subjects given 450 mg ABT-773 (n = 9) than in CYP3A5-positive subjects with identical doses (n = 8). The relationship for AUC(t) was statistically significant both after a single dose (geometric mean and 95% confidence interval [CI], 5.0 microg.h/mL [3.9-6.4 microg.h/mL] versus 2.8 microg.h/mL [1.8-4.3 microg.h/mL]; P =.03) and on the fifth day of twice-daily dosing (12.4 microg.h/mL [8.7-17.6 microg.h/mL] versus 7.4 microg.h/mL [5.5-9.8 microg.h/mL], P =.04). The relationship for C(max) was statistically significant after a single dose (1220 microg/mL [867-1167 microg/mL] versus 727 microg/mL [506-1044 microg/mL], P =.04) and showed a trend in the same direction on the fifth day of twice-daily dosing (2566 microg/mL [1813-3631 microg/mL] versus 1621 microg/mL [1122-2343 microg/mL], P =.07). In contrast, AUC(t) and C(max) were not significantly different between CYP3A5-positive and CYP3A5-negative individuals given 150 mg or 300 mg ABT-773. ABT-773 plasma levels did not trend with MDR-1 genotypes. These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose-dependent.