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CYP3A5 Genotype has a Dose‐dependent Effect on ABT‐773 Plasma Levels
Author(s) -
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
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.01.013
Subject(s) - cyp3a5 , cyp3a , pharmacokinetics , genotype , pharmacology , confidence interval , cyp2d6 , p glycoprotein , medicine , pharmacogenetics , chemistry , biology , cytochrome p450 , antibiotics , genetics , multiple drug resistance , metabolism , gene
Background 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. Objective 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. Methods 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. Results 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 μg · h/mL [3.9–6.4 μg · h/mL] versus 2.8 μg · h/mL [1.8–4.3 μg · h/mL]; P = .03) and on the fifth day of twice‐daily dosing (12.4 μg · h/mL [8.7–17.6 μg · h/mL] versus 7.4 μg · h/mL [5.5–9.8 μg · h/mL], P = .04). The relationship for C max was statistically significant after a single dose (1220 μg/mL [867–1167 μg/mL] versus 727 μg/mL [506–1044 μg/mL], P = .04) and showed a trend in the same direction on the fifth day of twice‐daily dosing (2566 μg/mL [1813–3631 μg/mL] versus 1621 μg/mL [1122–2343 μg/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. Conclusions These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose‐dependent. Clinical Pharmacology & Therapeutics (2004) 75 , 516–528; doi: 10.1016/j.clpt.2004.01.013