Interaction of disulfiram with antiretroviral medications: Efavirenz increases while atazanavir decreases disulfiram effect on enzymes of alcohol metabolism

Abstract

Background and Objectives Alcohol abuse complicates treatment of HIV disease and is linked to poor outcomes. Alcohol pharmacotherapies, including disulfiram (DIS), are infrequently utilized in co-occurring HIV and alcohol use disorders possibly related to concerns about drug interactions between antiretroviral (ARV) medications and DIS. Method This pharmacokinetics study (n=40) examined the effect of DIS on efavirenz (EFV), ritonavir (RTV), or atazanavir (ATV) and the effect of these ARV medications on DIS metabolism and aldehyde dehydrogenase (ALDH) activity which mediates the DIS-alcohol reaction. Results EFV administration was associated with decreased S-Methyl-N-N-diethylthiocarbamate (DIS carbamate), a metabolite of DIS (p=0.001) and a precursor to the metabolite responsible for ALDH inhibition, S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO). EFV was associated with increased DIS inhibition of ALDH activity relative to DIS alone administration possibly as a result of EFV-associated induction of CYP 3A4 which metabolizes the carbamate to DETC-MeSO (which inhibits ALDH). Conversely, ATV co-administration reduced the effect of DIS on ALDH activity possibly as a result of ATV inhibition of CYP 3A4. DIS administration had no significant effect on any ARV studied. Discussion/Conclusions ATV may render DIS ineffective in treatment of alcoholism. Future Directions DIS is infrequently utilized in HIV-infected individuals due to concerns about adverse interactions and side effects. Findings from this study indicate that, with ongoing clinical monitoring, DIS should be reconsidered given its potential efficacy for alcohol and potentially, cocaine use disorders, that may occur in this population.

The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder

“…For example, the oral concentrate formulation of sertraline contains 12% alcohol, and the oral solution of ritonavir contains 43% alcohol. Ritonavir and other antiretroviral medications can also interact with disulfiram and affect disulfiram levels through cytochrome P450 3A4 isoenzymes (McCance-Katz et al 2014). In addition, the combination of disulfiram and metronidazole has been associated with psychosis and a confusional state (Rothstein and Clancy 1969), although psychosis has also been reported with disulfiram independent of concomitant metronidazole use (Larson et al 1992).…”

Predicting drug interactions in addiction treatment

“…Disulfiram is a weak inhibitor of CYP2C9 metabolism and an inhibitor of ALDH, which converts acetaldehyde to acetate in alcohol metabolism. The increased concentration of acetaldehyde that occurs when alcohol is ingested with disulfiram causes the ‘aldehyde reaction’, an unpleasant combination of symptoms that act as a deterrent to alcohol consumption . Disulfiram can enhance warfarin's anticoagulant effect, potentially through inhibiting the hepatic synthesis of prothrombin.…”

“…The potential interactions between DOA and their therapies and antiretroviral medications for HIV are numerous. Atazanavir (a CYP3A4 inhibitor) has been associated with a lack of ALDH inhibition, indicating that disulfiram may be less effective at causing the aldehyde reaction if given with atazanavir . The clinical significance of these effects is not established .…”

“…Atazanavir (a CYP3A4 inhibitor) has been associated with a lack of ALDH inhibition, indicating that disulfiram may be less effective at causing the aldehyde reaction if given with atazanavir . The clinical significance of these effects is not established . Co‐administration of buprenorphine and atazanavir may cause sedation .…”

“…The increased concentration of acetaldehyde that occurs when alcohol is ingested with disulfiram causes the 'aldehyde reaction', an unpleasant combination of symptoms that act as a deterrent to alcohol consumption. 22,23 Disulfiram can enhance warfarin's anticoagulant effect, potentially through inhibiting the hepatic synthesis of prothrombin. Hence, monitoring and adjustment of warfarin dosage may be necessary if disulfiram and warfarin are co-administered.…”