ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment.
OBJECTIVE
The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment.


METHODS
Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam.


RESULTS
The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity.


CONCLUSIONS
In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.
Crettol
Séverine
S
Unité de Biochimie et Psychopharmacologie Clinique, Centre de Neurosciences Psychiatriques, Département de Psychiatrie-Centre Hospitalier Universitaire Vaudois, Hôpital de Cery, Prilly-Lausanne, Switzerland.
Déglon
Jean-Jacques
JJ
Besson
Jacques
J
Croquette-Krokar
Marina
M
Hämmig
Robert
R
Gothuey
Isabelle
I
Monnat
Martine
M
Eap
Chin B
CB
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008691:Methadone / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D008875:Middle Aged; D009293:Opioid-Related Disorders / Q000534:rehabilitation; D027361:Organic Anion Transporters / Q000235:genetics*; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D013237:Stereoisomerism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; D020033:Protein Isoforms; D003577:Cytochrome P-450 Enzyme System; D008691:Methadone