A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment.
OBJECTIVE
To assess CYP2D6 activity and genotype in a group of patients undergoing methadone maintenance treatment (MMT).


METHODS
Blood samples from 34 MMT patients were genotyped by a polymerase chain reaction-based method, and results were compared with CYP2D6 phenotype (n = 28), as measured by the molar metabolic ratio (MR) of dextromethorphan (DEX)/dextrorphan (DOR) in plasma.


RESULTS
Whereas 9% of patients (3/34) were poor metabolizers (PM) by genotype, 57% (16/28) were PM by phenotype (P < 0.005). Eight patients, who were genotypically extensive metabolizers (EM), were assigned as PM by their phenotype. The number of CYP2D6*4 alleles and sex were significant determinants of CYP2D6 activity in MMT patients, whereas other covariates (methadone dose, age, weight) did not contribute to variation in CYP2D6 activity.


CONCLUSIONS
There was a discordance between genotype and in vivo CYP2D6 activity in MMT patients. This finding is consistent with inhibition of CYP2D6 activity by methadone and may have implications for the safety and efficacy of other CYP2D6 substrates taken by MMT patients.
Shiran
M R
MR
Molecular Pharmacology and Pharmacogenetics, Division of Clinical Sciences (South), University of Sheffield, and Community Health Sheffield (CHS) Substance Misuse Services, Sheffield, UK.
Chowdry
J
J
Rostami-Hodjegan
A
A
Ellis
S W
SW
Lennard
M S
MS
Iqbal
M Z
MZ
Lagundoye
O
O
Seivewright
N
N
Tucker
G T
GT
D000328:Adult; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008691:Methadone / Q000627:therapeutic use*; D008875:Middle Aged; D009294:Narcotics / Q000627:therapeutic use*; D009293:Opioid-Related Disorders / Q000201:enzymology* / Q000235:genetics / Q000534:rehabilitation; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D012044:Regression Analysis; D015813:Substance Abuse Detection; D016482:Urinalysis
D009294:Narcotics; D019389:Cytochrome P-450 CYP2D6; D008691:Methadone