Methadone Pharmacogenetics: CYP2B6 Polymorphisms Determine Plasma Concentrations, Clearance, and Metabolism

Abstract

Background: Interindividual variability in methadone disposition remains unexplained, and methadone accidental overdose in pain therapy is a significant public health problem. Cytochrome P4502B6 (CYP2B6) is the principle determinant of clinical methadone elimination. The CYP2B6 gene is highly polymorphic, with several variant alleles. CYP2B6.6, the protein encoded by the CYP2B6*6 polymorphism, deficiently catalyzes methadone metabolism in vitro. This investigation determined the influence of CYP2B6*6, and other allelic variants encountered, on methadone concentrations, clearance, and metabolism.

Methods: Healthy volunteers in genotype cohorts CYP2B6*1/*1 (n = 21), CYP2B6*1/*6 (n = 20), and CYP2B6*6/*6 (n = 17), and also CYP2B6*1/*4 (n = 1), CYP2B6*4/*6 (n = 3), and CYP2B6*5/*5 (n = 2) subjects, received single doses of IV and oral methadone. Plasma and urine methadone and metabolite concentrations were determined by tandem mass spectrometry.

Results: Average S-methadone apparent oral clearance was 35 and 45% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R-methadone apparent oral clearance was 25 and 35% lower in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively, compared with CYP2B6*1/*1. R- and S-methadone apparent oral clearance was threefold and fourfold greater in CYP2B6*4 carriers. IV and oral R- and S-methadone metabolism was significantly lower in CYP2B6*6 carriers compared with that of CYP2B6*1 homozygotes and greater in CYP2B6*4 carriers. Methadone metabolism and clearance were lower in African Americans in part because of the CYP2B6*6 genetic polymorphism.

Conclusions: CYP2B6 polymorphisms influence methadone plasma concentrations, because of altered methadone metabolism and thus clearance. Genetic influence is greater for oral than IV methadone and S- than R-methadone. CYP2B6 pharmacogenetics explains, in part, interindividual variability in methadone elimination. CYP2B6 genetic effects on methadone metabolism and clearance may identify subjects at risk for methadone toxicity and drug interactions.

Conflict of interest statement

No author has any conflict of interest

Figures

Figure 1

Influence of CYP2B6 genotype on the disposition and metabolism of oral methadone. Subjects received 11.0 mg oral methadone HCl (9.9 mg free base). Shown are plasma concentrations of (A) R-methadone, (B) S-methadone, (C) R-EDDP, and (D) S-EDDP and (E) R/S-methadone concentration ratios. Each data point is the mean ± SD. Some SD values are omitted for clarity. Genotype cohorts were CYP2B6*1/*1 (n=21), CYP2B6*1/*6 (n=20), CYP2B6*6/*6 (n=17) and CYP2B6*4/X (n=4, with results for one CYP2B6*1/*4 and three CYP2B6*4/*6 subjects combined). EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine

Figure 2

Influence of CYP2B6 genotype on the disposition and metabolism of intravenous methadone. Subjects received 6.0 mg intravenous methadone HCl (5.4 mg free base). Shown are plasma concentrations of (A) R-methadone, (B) S-methadone, (C) R-EDDP, and (D) S-EDDP. Each data point is the mean ± SD. Some SD values are omitted for clarity. Genotype cohorts were CYP2B6*1/*1 (n=21), CYP2B6*1/*6 (n=20), CYP2B6*6/*6 (n=17) and CYP2B6*4/X (n=4, with results for one CYP2B6*1/*4 and three CYP2B6*4/*6 subjects combined). EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine

Figure 3

Influence of minor CYP2B6 alleles on the disposition and metabolism of intravenous and oral methadone. Subjects received 6.0 mg intravenous methadone HCl and 11.0 mg oral methadone HCl. Shown are plasma concentrations of (A) R-methadone, (B) S-methadone, (C) R-methadone, and (D) S-methadone after intravenous (A,B) and oral (C,D) dosing. Each data point is the mean. Genotype cohorts were CYP2B6*1/*1 (n=21), CYP2B6*1/*4 (n=1), CYP2B6*4/*6 (n=3) and CYP2B6*5/*5 (n=2).

Figure 4

Influence of CYP2B6*6 genotype on methadone clearance. Shown are the systemic clearances for intravenous (A) R-methadone and (B) S-methadone, and the apparent oral clearances for oral (C) R-methadone and (D) S-methadone, as box plots (solid line within the box is the median, dash line within the box is the mean, box boundaries are the 25th and 75th percentiles, error bars are the 10th and 90th percentiles, and individual points are outliers). *Significantly different from wild-type (CYP2B6*1/*1), p<0.05.

Figure 5

Influence of CYP2B6*6 genotype on methadone metabolism. Shown is the plasma concentration vs time AUC ratio for EDDP/methadone for intravenous (A) R-methadone and (B) S-methadone, and oral (C) R-methadone and (D) S-methadone, and the EDDP formation clearance for intravenous (E) R-methadone and (F) S-methadone, and oral (G) R-methadone and (H) S-methadone. Results are shown as box plots (solid line within the box is the median, dash line within the box is the mean, box boundaries are the 25th and 75th percentiles, error bars are the 10th and 90th percentiles, and individual points are outliers). *Significantly different from wild-type (CYP2B6*1/*1), p<0.05. EDDP = 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine