Influence of ABCB1 C3435T polymorphism on the pharmacokinetics of lansoprazole and gastroesophageal symptoms in Japanese renal transplant recipients classified as CYP2C19 extensive metabolizers and treated with tacrolimus.
OBJECTIVE
Lansoprazole and tacrolimus are substrates of ATP binding cassette (ABC) transporters such as P-glycoprotein (ABCBI/multidrug resistance 1) and cytochrome P450 (CYP). The purpose of this study was to investigate the implication of the ABCB1 C3435Tpolymorphism on the pharmacokinetics of (R)-lansoprazole, the major enantiomer, in CYP2C19 extensive metabolizers (EMs) and on gastroesophageal symptoms in renal transplant recipients receiving tacrolimus.


METHODS
24 recipients who were CYP2C19 EMs were studied.


METHODS
Oral administration of 30 mg lansoprazole was started 2 days before transplantation. On Day 2 before and Day 28 after transplantation, the plasma concentrations of (R)-lansoprazole and tacrolimus were measured.


RESULTS
Pretransplantation, there were no significant differences in the pharmacokinetic parameters of (R)-lansoprazole between the 3 ABCBI C3435T genotypes. However, after renal transplantation, the peak plasma concentration (Cma ) and area under the plasma concentration-time curve (AUCO-24) of (R)-lansoprazole in patients with the ABCB1 C3435T C allele significantly increased, but not in patients with the TT genotype. These pharmacokinetic variations in (R)-lansoprazole did not influence the AUC of tacrolimus. There were no significant differences in the frequency of gastroesophageal symptoms among the three ABCB] C3435Tgenotypes.


CONCLUSIONS
(R)-lansoprazole concentrations significantly increased in CYP2C19 extensive metabolizers with the ABCB1 C3435T C allele, but not TT genotype, after renal transplantation. However, the clinical relevance of this observation may be minor because these pharmacogenetic changes were not associated with the occurrence of gastroesophageal complications.
Miura
M
M
Department of Pharmaceutical Science, Akita University School of Medicine, Akita, Japan.
Satoh
S
S
Tada
H
H
Saito
M
M
Kagaya
H
H
Inoue
K
K
Sagae
Y
Y
Kanno
S
S
Ishikawa
M
M
Habuchi
T
T
Suzuki
T
T
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000284:Administration, Oral; D000328:Adult; D000483:Alleles; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D044466:Asian People / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D064748:Dexlansoprazole; D005260:Female; D005764:Gastroesophageal Reflux / Q000188:drug therapy* / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D007564:Japan; D016030:Kidney Transplantation; D064747:Lansoprazole; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000897:Anti-Ulcer Agents; D007166:Immunosuppressive Agents; D027361:Organic Anion Transporters; D064747:Lansoprazole; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D064748:Dexlansoprazole; D016559:Tacrolimus