Influence of cytochrome P450 (CYP) 3A5 polymorphisms on the pharmacokinetics of lansoprazole enantiomers in CYP2C19 extensive metaboliser renal transplant recipients.
OBJECTIVE
Lansoprazole is extensively metabolised by cytochrome P450 (CYP) 2C19 and CYP3A4. The purpose of this study was to evaluate the effects of CYP3A5 polymorphism (A6986G) on the pharmacokinetics of lansoprazole enantiomers in renal transplant recipients who are CYP2C19 extensive metabolisers (EMs).


METHODS
Among 40 Japanese CYP2C19 EMs, 20 had the CYP3A5*1 allele (*1/*1 in two subjects and *1/*3 in 18 subjects) and 20 had the CYP3A5*3/*3 genotype. After repeated oral doses of racemic lansoprazole 30mg once daily for 28 days, plasma concentrations of lansoprazole enantiomers were determined using high performance liquid chromatography.


RESULTS
The mean area under the plasma concentration-time curves from 0 to infinity (AUC(infinity)) of (R)- and (S)-lansoprazole in recipients with the CYP3A5*1 allele were 3145 and 384 ng * h/mL, respectively, compared with 4218 and 587 ng * h/mL in recipients with the CYP3A5*3/*3 genotype. The AUC(infinity) and the maximum plasma concentration of (R)- and (S)-lansoprazole in subjects with the CYP3A5*3/*3 genotype were greater than subjects with CYP3A5*1/*1 + *1/*3 alleles. The mean R/S ratio for AUC of lansoprazole in each CYP3A5 genotype group was the same (12.6).


CONCLUSIONS
Our findings show that CYP3A5 genotype is not an important determinant of enantioselective disposition of lansoprazole. Based on our results and those of previous studies, the enantioselective disposition of lansoprazole appears to be primarily influenced by enantioselective metabolism by CYP2C19 rather than by CYP3A.
Miura
Masatomo
M
Department of Pharmacy, Akita University Hospital, Akita, Japan. m-miura@hos.akita-u.ac.jp
Inoue
Kazuyuki
K
Satoh
Shigeru
S
Itoh
Yoshihiko
Y
Kagaya
Hideaki
H
Tada
Hitoshi
H
Tanaka
Yorihisa
Y
Habuchi
Tomonori
T
Suzuki
Toshio
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000890:Anti-Infective Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood; D016030:Kidney Transplantation; D064747:Lansoprazole; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D009173:Mycophenolic Acid / Q000097:blood; D011110:Polymorphism, Genetic; D013237:Stereoisomerism; D016559:Tacrolimus / Q000097:blood
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000890:Anti-Infective Agents; D007166:Immunosuppressive Agents; D064747:Lansoprazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D009173:Mycophenolic Acid; D016559:Tacrolimus