Hepatitis C Virus Infection Influences the S-Methadone Metabolite Plasma Concentration

Abstract

Background and ObjectivesHeroin-dependent patients typically contract hepatitis C virus (HCV) at a disproportionately high level due to needle exchange. The liver is the primary target organ of HCV infection and also the main organ responsible for drug metabolism. Methadone maintenance treatment (MMT) is a major treatment regimen for opioid dependence. HCV infection may affect methadone metabolism but this has rarely been studied. In our current study, we aimed to test the hypothesis that HCV may influence the methadone dosage and its plasma metabolite concentrations in a MMT cohort from Taiwan.MethodsA total of 366 MMT patients were recruited. The levels of plasma hepatitis B virus (HBV), HCV, human immunodeficiency virus (HIV) antibodies (Ab), liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT), as well as methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) were measured along with the urine morphine concentration and amphetamine screening.ResultsOf the 352 subjects in our cohort with HCV test records, 95% were found to be positive for plasma anti-HCV antibody. The liver functional parameters of AST (Wilcoxon Rank-Sum test, P = 0.02) and ALT (Wilcoxon Rank-Sum test, P = 0.04), the plasma methadone concentrations (Wilcoxon Rank-Sum test, P = 0.043) and the R-enantiomer of methadone concentrations (Wilcoxon Rank-Sum test, P = 0.032) were significantly higher in the HCV antibody-positive subjects than in the HCV antibody-negative patients, but not the S-EDDP/methadone dose ratio. The HCV levels correlated with the methadone dose ( = 14.65 and 14.13; P = 0.029 and 0.03) and the S-EDDP/methadone dose ratio ( = −0.41 and −0.40; P = 0.00084 and 0.002) in both univariate and multivariate regression analyses.ConclusionsWe conclude that HCV may influence the methadone dose and plasma S-EDDP/methadone dose ratio in MMT patients in this preliminary study.

Toward precision prescribing for methadone: Determinants of methadone deposition

“…This study is limited since HCV status was only determined based upon antibody testing, which does not differentiate between active and resolved infections. Despite these limitations, both studies are in agreement that HCV influences plasma methadone concentration in OUD patients on methadone [67,68]. In contrast to the above-mentioned studies, we did not observe a significant effect of fibrosis stage on methadone metabolism.…”

“…However, this investigation has several weaknesses including lack of clarity as to how HCV status was defined and determined, measurements limited to peak methadone concentration, a homogeneous participant population consisting of males of limited racial and ethnic diversity, and absence of cirrhotic participants [67]. In a Taiwanese population, Wu et al [68] found that total plasma methadone and (R)-methadone concentrations were significantly higher in HCV seropositive compared with HCV seronegative participants. This study is limited since HCV status was only determined based upon antibody testing, which does not differentiate between active and resolved infections.…”

Pharmacogenomics study in a Taiwanese methadone maintenance cohort

“…In our previous studies, the SNPs on CYP2B6 were significantly associated with plasma S -methadone concentration, the ratio of S -methadone/methadone dose, and the S -methadone clearance [6]. We also found that the CYP2B6 has a higher level of activity in the HCV-positive patients [20]. SNPs in CYP3A4 were significantly associated with COWS, TESS, and betel nut use [12].…”

Chemokine IP-10 is correlated with cardiac responses and status of infection with HIV and HCV in methadone maintenance patients

“…A higher initial methadone dose (P = 0.038), higher plasma concentrations of (R,S)-methadone (P = 0.038) and R-methadone (P = 0.028), lower ratio of S-EDDP/methadone dose (P = 0.043), higher levels of AST (P = 0.048) and ALT (P = 0.046), and a longer addiction duration (P b 0.0001) were found in the HIV(+)/HCV(+) or HCV(+) patients than the HIV(−)/HCV(−) patients ( Table 1). The results of urine morphine test, which was used as a surrogate indicator for the effectiveness of opioid dependence treatment [6], were not statistically different among subjects grouped by their status of HIV and/or HCV infection.…”