Enantioselective disposition of lansoprazole in extensive and poor metabolizers of CYP2C19

Abstract

The effect of CYP2C19 genetic polymorphism on the enantioselective disposition of lansoprazole seems to be less significant than the effect on omeprazole and pantoprazole. The disposition of lansoprazole enantiomers appears to be influenced by enantioselective protein binding and by enantioselective metabolism of lansoprazole.

Enantioselective Disposition of Lansoprazole and Rabeprazole in Human Plasma

“…This AUC ratio is nearly the same as the ratios seen in CYP2C19 EM healthy subjects. 17,23) However, the t max value of ( R)-and (S )-lansoprazole in renal transplant recipients (3.9 and 3.3 h, respectively) is much longer than t max values in healthy subjects (1.9 and 1.7 h, respectively) who do not consume any food for 12 h prior to experiments. 23) These data suggest that the absorption of lansoprazole is greatly aŠected by digestion, since lansoprazole is an enteric coated product.…”

“…26) There was no diŠerence in the C max of renal transplant recipients between ( R)-and (S )-rabeprazole (186 vs. 200 ng/ml, respectively) ( Table 1). Although the enantioselective disposition of lansoprazole in renal transplant recipients is similar to that in CYP2C19 EM healthy subjects, 17,23) the enantioselective disposition of rabeprazole in renal transplant recipients diŠers from that in healthy subjects. 24) Further studies are necessary in order to examine the diŠerence in absorption andˆrst pass metabolism of rabeprazole enantiomers between renal transplant recipients and healthy subjects.…”

“…126 (2006) enantiomers in human plasma have been studied by high-performance liquid chromatography (HPLC) using chiral columns (Chiralcel OD or Chiralpak AS, Daicel Chemical Co.). 17,18) One HPLC method for the simultaneous determination of lansoprazole enantiomers and their metabolites has been reported; however, this method was only suitable for the analysis of in vitro microsomal samples and could not be applied to human plasma samples. 19 …”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…The AUCs of both omeprazole and lansoprazole are 4-to 15-fold higher in PMs than in homozygous EMs, whereas heterozygous EMs are intermediate between the two (2-to 3-fold higher than homozygous EMs) (Furuta et al, 1999a(Furuta et al, ,b, 2001cIeiri et al, 2001;Shirai et al, 2001;Cho et al, 2002;Kim et al, 2002;Shirai et al, 2002). With multiple dosing, the increase in AUC of omeprazole (but not of lansoprazole or pantoprazole) decreases to ϳ2-fold in EMs, due to inhibition of its own metabolism by CYP2C19 Shirai et al, 2001).…”

The effect of CYP2C19 activity on pharmacokinetics of lansoprazole and its active metabolites in healthy subjects

“…Formation of the 5-hydroxy metabolite is mainly by cytochrome P450 2C19 (CYP2C19), whereas CYP3A4 is involved in the formation of sulfone (Andersson, 1996;Pearce et al, 1996). CYP2C19, also known as S-mephenytoin 4-hydroxylase, shows genetically determined polymorphism, which is expected to affect the pharmacokinetics of lansoprazole (Kim et al, 2002;Miura et al, 2004;Liu et al, 2005). The CYP2C19 gene is located on chromosome 10p, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed, in addition to the wild-type allele CYP2C19*1, two mutant alleles, CYP2C19*2 and CYP2C19*3, that could be responsible for genetically deficient metabolic activity (De Morais et al, 1994a, 1994b.…”