Effects of the CYP3A5 genetic polymorphism on the pharmacokinetics of diltiazem.
BACKGROUND
The cytochrome P450 (CYP) 3A subfamily plays an important role in the metabolism of various endogenous and exogenous compounds. Among CYP3A subfamily members, CYP3A5 is polymorphically expressed and the CYP3A5*3 and CYP3A5*6 alleles are known not to express functional CYP3A5. Thus, these mutant alleles are thought to be responsible for interindividual variability of CYP3A activity.


METHODS
Subjects possessing CYP3A5*1/*1, *1/*3 or *3/*3 received oral administration of diltiazem hydrochloride (60 mg), and plasma and urinary concentrations of diltiazem and its metabolite N-desmethyldiltiazem were measured. Before drug intake, cortisol metabolic clearance in each subject was measured to estimate in vivo CYP3A4 activity.


RESULTS
The mean values of total oral diltiazem clearance of subjects with *1/*1, *1/*3 and *3/*3 were 183.4 +/- 39.4, 197.9 +/- 49.6 and 293.6 +/- 141.1 (l/h), respectively, and were not significantly different among the 3 genotype groups. The cortisol metabolic clearance was not significantly different among the three genotype groups, indicating that the CYP3A4 activity is not significantly different.


CONCLUSIONS
The results suggest that CYP3A5*3 has only a minor effect on the pharmacokinetics and metabolism of diltiazem. Although our results did not indicate significance of CYP3A5, the effects of CYP3A5*3 on the metabolism of other CYP3A substrates remain to be investigated.
Yamamoto
Takehito
T
Department of Pharmacy, University of Tokyo Hospital, Hongo, Bunkyo-ku, Japan.
Kubota
Takahiro
T
Ozeki
Takeshi
T
Sawada
Mika
M
Yokota
Shin-ichi
S
Yamada
Yasuhiko
Y
Kumagai
Yuji
Y
Iga
Tatsuji
T
D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004110:Diltiazem / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*
D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D004110:Diltiazem; D006854:Hydrocortisone