Genetic polymorphisms of CYP2A6 affect the in-vivo pharmacokinetics of pilocarpine.
OBJECTIVE
Pilocarpine is metabolized to pilocarpic acid by plasma esterase and to 3-hydroxypilocarpine by CYP2A6. The objective of this study was to identify the determinants of interindividual differences in pilocarpine pharmacokinetics after oral administration and to investigate the possible involvement of genetic polymorphisms of CYP2A6.


METHODS
The pharmacokinetic parameters of pilocarpine, pilocarpic acid, and 3-hydroxypilocarpine after oral administration of pilocarpine hydrochloride in 28 Japanese participants were calculated based on the data obtained from two phase-1 clinical studies. Probit analysis was carried out for the pharmacokinetic parameters, and participants were accordingly classified into two groups: poor metabolizers and nonpoor metabolizers of pilocarpine. The poor metabolizers were genotyped for CYP2A6, and the pharmacokinetic parameters in this group were compared with those in the nonpoor metabolizers.


RESULTS
Relatively large interindividual differences were observed in the pharmacokinetic parameters of pilocarpine, pilocarpic acid, and 3-hydroxypilocarpine. Probit analysis of the pharmacokinetic parameters revealed that seven of the 28 participants exhibited significantly low plasma concentrations and urinary recovery of 3-hydroxypilocarpine and were classified as poor metabolizers. Genotyping analysis revealed that these poor metabolizers had two inactive CYP2A6 alleles, CYP2A6*4A, CYP2A6*7, CYP2A6*9, or CYP2A6*10. The apparent pilocarpine clearance was significantly lower in the poor metabolizers than in the nonpoor metabolizers (P<0.05).


CONCLUSIONS
We demonstrated that CYP2A6 genotype is a contributor to pilocarpine pharmacokinetics, although the impact of the CYP2A6 polymorphism may be pharmacologically and toxicologically tolerable.
Endo
Takuro
T
Department of Pharmacokinetics Research, R&D, Kissei Pharmaceutical Co. Ltd., Nagano, Japan. takuro_endo@pharm.kissei.co.jp
Nakajima
Miki
M
Fukami
Tatsuki
T
Hara
Yoshiki
Y
Hasunuma
Tomoko
T
Yokoi
Tsuyoshi
T
Momose
Yasunori
Y
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065637:Cytochrome P-450 CYP2A6; D006801:Humans; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010862:Pilocarpine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D011110:Polymorphism, Genetic
C520141:3-hydroxypilocarpine; D018721:Muscarinic Agonists; D010862:Pilocarpine; C029118:pilocarpic acid; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6