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

The American Journal on Addictions, XX: 1–8, 2013Copyright 2013 American Academy of Addiction PsychiatryISSN: 1055-0496 print / 1521-0391 onlineDOI: 10.1111/j.1521-0391.2013.12081.x Interaction of Disulfiram with Antiretroviral Medications:Efavirenz Increases While Atazanavir Decreases DisulfiramEffect on Enzymes of Alcohol Metabolism Elinore F. McCance‐Katz, MD, PhD,1 Valerie A. Gruber, PhD,1 George Beatty, MD, MPH,1Paula Lum, MD,1 Qing Ma, PhD,2,3 Robin DiFrancesco,2,3 Jill Hochreiter,2,3 Paul K. Wallace,PhD,4 Morris D. Faiman, PhD,5 Gene D. Morse, PhD2,31University of California San Francisco, San Francisco, California2HIV Clinical Pharmacology Research Program, Translational Pharmacology Research Core, NYS Center of Excellence inBioinformatics and Life Sciences, University at Buffalo, SUNY, Buffalo, New York3School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York4Department of Flow and Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York5Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas Background and Objectives: Alcohol abuse complicates treatment alcohol and potentially, cocaine use disorders, that may occur in this of HIV disease and is linked to poor outcomes. Alcohol population. (Am J Addict 2013;XX:000–000) pharmacotherapies, including disulfiram (DIS), are infrequentlyutilized in co‐occurring HIV and alcohol use disorders possiblyrelated to concerns about drug interactions between antiretroviral(ARV) medications and DIS.
Method: This pharmacokinetics study (n ¼ 40) examined the effectof DIS on efavirenz (EFV), ritonavir (RTV), or atazanavir (ATV) and the effect of these ARV medications on DIS metabolism and aldehydedehydrogenase (ALDH) activity which mediates the DIS‐alcoholreaction.
Disulfiram (DIS; Antabuse®) is a U.S. Food and Drug Results: EFV administration was associated with decreased S‐ Administration (FDA) approved pharmacotherapy for the Methyl‐N‐N‐diethylthiocarbamate (DIS carbamate), a metabolite of treatment of alcohol dependence. DIS is a relatively irrevers- DIS (p ¼ .001) and a precursor to the metabolite responsible for ible inhibitor of sulfhydryl‐containing enzymes.1 The target ALDH inhibition, S‐methyl‐N,N‐diethylthiolcarbamate sulfoxide(DETC–MeSO). EFV was associated with increased DIS inhibition enzyme for the pharmacologic effect of DIS in the treatment of of ALDH activity relative to DIS alone administration possibly as a alcohol addiction is aldehyde dehydrogenase (ALDH). This result of EFV‐associated induction of CYP 3A4 which metabolizes enzyme converts acetaldehyde to acetate in alcohol metabo- the carbamate to DETC–MeSO (which inhibits ALDH). Conversely, lism. The increased concentration of acetaldehyde after alcohol ATV co‐administration reduced the effect of DIS on ALDH activity ingestion in the presence of DIS is responsible for the DIS‐ possibly as a result of ATV inhibition of CYP 3A4. DIS administrationhad no significant effect on any ARV studied.
alcohol reaction. This reaction is characterized by flushing, Discussion/Conclusions: ATV may render DIS ineffective in weakness, nausea, tachycardia, and in some instances, hypotension.2 In addition to its use as a deterrent to alcohol Future Directions: DIS is infrequently utilized in HIV‐infected consumption, DIS has shown promise as a potential individuals due to concerns about adverse interactions and side pharmacotherapy for cocaine abuse.3 Clinical trials have effects. Findings from this study indicate that, with ongoing clinicalmonitoring, DIS should be reconsidered given its potential efficacy for shown decreases in cocaine and alcohol use with DIS 250 mgdaily administration 4 while human laboratory studies haveshown significant decreases in cocaine “high” and “rush” whencocaine was administered by the intravenous route in a double‐ Received December 18, 2012; revised March 6, 2013; accepted blind, randomized study in which either DIS 0, 62.5 mg or 250 mg daily was administered chronically.5 Address correspondence to Dr. McCance‐Katz, Chief Medical Officer, Substance Abuse and Mental Health Services Administra- Substance abuse is common in those with HIV infection6,7 tion, 1 Choke Cherry Rd., Room 8‐1055, Rockville, MD 20857.
and the availability of addiction pharmacotherapy for this E‐mail: [email protected].
population is important. For example, the clinical benefit ofopioid therapies including methadone and buprenorphine to treat opioid dependence, often in injection drug users who netics studies in which a within‐subjects analysis was used have contracted HIV infection through high risk injection to determine the effect of ARV combined with DIS on practices, has been clearly demonstrated.8 However, med- ALDH activity. A between‐subjects analysis was used to ications to treat alcoholism are used infrequently although examine the effect of ARVon the DIS metabolite, S‐Methyl‐ alcohol abuse is a significant problem complicating the N‐N‐diethylthiocarbamate (DIS carbamate), and the effect treatment of HIV disease and has been linked to poor HIV outcomes.9–11 The potential of DIS for adverse drug–drug Each study component was conducted independently and interactions with antiretroviral medications (ARV) is a was open‐label to increase the safety of the study participants.
significant concern that could be a factor in diminishing Participants in the DIS alone group received DIS 62.5 mg daily consideration of use of this medication in those with for 4 days followed by a pharmacokinetics study over 10 hours. Participants were then placed on DIS 250 mg daily DIS must be bioactivated through a series of intermediates, and received this medication for 4 days followed by another ultimately forming S‐methyl‐N,N‐diethylthiolcarbamate sulf- pharmacokinetics study. Blood samples for DIS alone oxide (DETC–MeSO), the metabolite proposed to be pharmacokinetics studies were collected at 0, .5, 1, 2, 4, 6, responsible for the in vivo inhibition of ALDH.12,13 8, and 10 hours. Volunteers who participated in the DIS/ARV Bioactivation of DIS to the active metabolite associated with studies were assigned to receive clinical doses of either EFV the DIS‐alcohol reaction, DETC–MeSO, occurs principally via 600 mg daily for 10 days or RTV 200 mg daily for 8 days or cytochrome P450 (CYP) 3A4/5, with contributions by ATV 400 mg daily for 8 days. Upon completion of the dosing CYP1A2, ‐2A6 and ‐2D6.14,15 Inhibition by DIS of CYP450 period for the ARV, either a 12 hour (RTV) or 24 hour (ATVor enzymes, mainly 2E116,17 and 1A2,18,19 and demethylation EFV) pharmacokinetics study was undertaken in which ARV function has been reported.20 Therefore, this study investigated samples were collected at 0, .5, 1, 1.5, 2, 4, 6, 8, 12, and any potential effect on CYP450 enzymes by DIS that might 24 hours (the latter sample for EFVand ATV studies). Once the alter the metabolism of ARV, specifically efavirenz (EFV), ARV pharmacokinetics study was completed, participants ritonavir (RTV), and atazanavir (ATV) since these ARV are began a 4 day course of DIS 62.5 mg daily with continued substrates of CYP3A4/5 and ‐2B6. Also important was the ARV medication followed by a second pharmacokinetics study determination of whether DIS would be efficacious as a in which both DIS and the ARV of interest were sampled as treatment for alcohol dependence when co‐administered with previously described. A 4 day washout of DIS with continued ARV that could potentially alter DIS metabolism. For example, ARV administration was followed by a dosing period of 4 days EFV has been reported to induce CYP3A4 activity21,22 while with DIS 250 mg daily. All medication ingestion was observed RTV is a potent inhibitor of CYP3A4.23 Therefore, the effects by study staff with the exception of EFV which is generally of ARV administration on DIS metabolism were also given in the evening when used for HIV treatment. Four days prior to the pharmacokinetics studies, EFV dosing waschanged to mornings and all dosing was observed. The finalpharmacokinetics study of ARV and DIS 250 mg was undertaken as described above. Blood samples for ALDHwere collected at baseline (prior to receiving any study Forty individuals participated in this project composed medications) and following completion of study medication of four separate pharmacokinetics study components with observed dosing (eg, Day 4 following DIS 62.5 mg daily and 10 participants enrolled in each component which included Day 4 following DIS 250 mg daily dosing for DIS alone and determination of pharmacokinetics for (1) DIS alone, (2) similarly following DIS administration in combination with DIS/EFV, (3) DIS/RTV, and (4) DIS/ATV. The study was ARV medications). Each ALDH sample was collected prior to reviewed and approved by the Institutional Review Board at DIS or DIS þ ARV dosing at the time of the pharmacokinetics the University of California San Francisco (UCSF) and is study. Adverse symptoms were recorded for all participants registered at (NCT00878306). Partic- using an Adverse Symptoms Checklist25 that queried for a ipants were healthy subjects with health status determined wide range of adverse experiences including changes in by medical history and physical examination, psychological energy, gastrointestinal symptoms, central nervous system testing (Mini‐International Neuropsychiatric Interview24), effects, genitourinary symptoms, and other somatic complaints laboratory testing, and cardiogram which were within scored for severity on an ordinal scale (0–3, with 0 ¼ not normal ranges at baseline (Table 1). Participants were present, 1 ¼ mild, 2 ¼ moderate, and 3 ¼ severe, maximum taking no other medications that might impact CYP 450 possible score ¼ 87). These ratings were administered at function. All participants were confirmed to have no baseline, following DIS administration, following ARV evidence of HIV infection (by HIV antibody and HIV viral administration, and following administration of ARV and load tests). Participants were tested for ALDH activity DIS concomitantly. Upon completion of study procedures, which is a marker of DIS ability to induce a DIS‐alcohol participants received a final physical examination and reaction (ie, whether DIS would be expected to be effective laboratory testing to assure that no clinically significant as a deterrent to alcohol use) and underwent pharmacoki- Disulfiram–Antiretroviral Medication Interactions ALK phosphate (U/L)Normal range: 42–98 U/L Total bilirubin (mg/dl)Normal range: .1–1.2 mg/dl Total protein (g/dl)Normal range: 6.4–8.3 g/dl Other race includes hispanic, native american, pacific islander, and multi‐racial individuals; ÃMean (SE), [] percent of sample affected; †p .01.
the flow cytometery laboratory at Roswell Park Cancer Institute for analysis. The blood samples were processed for All blood samples were collected in heparinized 6 ml vacutainer tubes. For drug concentration determination,plasma was separated by centrifugation and stored at À70°C until shipment. Plasma samples were shipped on dry ice to the ALDH activity in peripheral blood mononuclear cells was University at Buffalo Translational Pharmacology Research measured using ALDEFLUOR™ Kits. These kits are routinely Core and kept at À70°C until assay. Samples were thawed prior used to identify stem and progenitor cells expressing high to assays which were conducted as described below. Blood levels of ALDH.26 Total and control ALDH measurements samples for ALDH determination were collected in heparin- were performed in triplicate. Cytofluorometric analysis was ized vacutainer tubes and shipped overnight on a cold pack to performed using a FACSCanto II (BD BioSciences, San Jose, CA) flow cytometer equipped with 408, 488, and 640 nm obtained at baseline and following DIS administration, ARV lasers. Monocytes were gated and the net ALDH activity administration or combined administration of ARV and DIS.
determined by subtracting control from total activity.
There was no evidence for clinically significant changes in QTinterval under any study condition (Table 1). Administration of S‐Methyl‐N‐N‐Diethylthiocarbamate (DIS Carbamate) DIS, ARV, or DIS concurrently with any of the ARV produced no significant changes in adverse symptoms from those DIS carbamate concentrations were determined using ultra performance liquid chromatography coupled to electrospraytandem mass spectrometry.27 S‐Methyl‐N‐N‐diethylthiocarba-mate reference standard (lot number ELZ‐125‐3, 98% purity) was used to prepare calibration standards and quality controlsand was supplied by Toronto Research Chemicals. RTV, ATV, and EFV were quantified using previously published simulta- Table 2A–C shows pharmacokinetic parameters for each of neous high‐performance liquid chromatography (HPLC) the ARValone or concurrent with either dose of DIS for 4 days.
Neither dose of DIS had a significant effect on any of thepharmacokinetic parameters examined including total expo- Pharmacokinetics and Statistical Analysis sure to ARV over time (AUCtau), clearance, maximum plasma Plasma DIS metabolite and ARV pharmacokinetics were concentration (Cmax), time to maximum plasma concentration evaluated for each subject. Standard non‐compartmental (Tmax), and elimination half‐life.
methods were used to estimate pharmacokinetic parametersincluding area under the concentration‐time curve (AUC Two indices of DIS activity in the presence of ARV medications were examined with simultaneous, chronic dosing 1/2) and oral clearance (CLss/F), where F of both the ARV of interest and DIS. The DIS intermediary the raw data (Phoenix 64, WinNonlin 6.3).
metabolite, DIS carbamate, is formed following metabolism via The Kruskal–Wallis test was used to determine the the CYP 450 enzyme system and, therefore, is one measure of significance of the differences in ARV pharmacokinetic the effect of ARV medications, which have the potential to alter CYP 450 function, on DIS efficacy. Table 3 shows a dose of DIS 62.5 and DIS 250 mg/d. Determination of differences in response for DIS pharmacokinetics parameters as demonstrated effects of ARVon DIS intermediary metabolite, DIS carbamate, by the DIS metabolite, DIS carbamate, for the DIS 62.5 mg pharmacokinetics parameters were also examined by Kruskal– daily dose versus the DIS 250 mg daily dose. A significant Wallis test. ALDH activity was analyzed using a within‐ effect of ARV administration on pharmacokinetics parameters subjects approach by paired t‐test with comparison of baseline for DIS 250 mg daily including Cmax, Cmin, and AUC0–10 and ALDH and ALDH activity following DIS or DIS/ARV for DIS 62.5 mg daily Cmax and AUC0–10 was observed. The administration. All differences were considered statistically differences were related to significantly lower DIS carbamate significant if the p‐value was .05 (2‐tailed). Comparisons of Cmax, Cmin, and AUC0–10 with EFV administration (Table 3, participant characteristics were made by one‐way ANOVA.
Fig. 1). The second measure of DIS activity was examination ofALDH activity. ALDH inhibition is the means by which alcoholmetabolism is attenuated resulting in a noxious reaction withalcohol consumption when clinical doses (DIS 250 mg daily) are utilized in the treatment of alcohol use disorders. Figure 2 shows reductions in ALDH activity when DIS 250 mg/d is There were no significant differences in age (range 34–45 administered alone (p ¼ .02) and represents a 44% decrease in years), weight (75–87 kg), gender (samples ranged from 30– ALDH activity in this sample. ALDH activity is also 60% women), or cigarette use between any of the groups (0–.1 significantly decreased when RTV 200 mg/d is administered packs per day; Table 1). All samples were comprised of healthy concurrently with DIS 250 mg/d (p ¼ .009) and represents a subjects and no diagnoses of medical, mental, or substance use 36% decrease in ALDH activity. ATV co‐administration with disorders were identified on completion of screening proce- DIS 250 mg/d resulted in a 16% reduction in ALDH activity dures. Laboratory indices of hepatic function (alanine (NS). EFV co‐administration with DIS 250 daily resulted in the aminotransferase (ALT), aspartate aminotransferase (AST), highest levels of ALDH inhibition at 52% (p ¼ .002).
alkaline phosphatase, and total protein) remained withinnormal ranges throughout the study period including baselinevalues, following ARV administration, DIS administration and combined ARV and DIS administration (Table 1). Totalbilirubin was significantly increased following ATV adminis- This study shows that DIS can be safely used with tration alone and in combination with DIS. Cardiograms were commonly prescribed ARV including RTV, ATV, and EFV.
Disulfiram–Antiretroviral Medication Interactions TABLE 2. Effect of disulfiram on antiretroviral medication pharmacokinetics A. Ritonavir (RTV) pharmacokinetics during disulfiram co‐administration B. Atazanavir (ATV) pharmacokinetics during disulfiram co‐administration C. Efavirenz (EFV) pharmacokinetics during disulfiram co‐administration ÃValues are the mean (standard error of the mean) for 10 subjects who participated in the study in each group, except that the discontinuous variable, Tmax, is given as DIS has no effect on the pharmacokinetics of any of these to DIS alone administration. ATV administration with DIS medications; therefore ARV dose adjustments when using DIS 250 mg daily was associated with a lack of DIS‐associated for treatment of substance use disorders in those receiving inhibition of ALDH activity. This indicates that DIS at standard these ARV should not be necessary. Two of the ARV studied clinical doses utilized in the treatment of alcohol use disorders had significant effects on DIS metabolism. EFV co‐adminis- is unlikely to be effective; that is, a DIS‐alcohol reaction may tration was associated with significant decreases in DIS not occur in an individual receiving an ATV‐containing carbamate and a moderate increase in ALDH inhibition relative regimen for HIV infection and DIS for an alcohol disorder.
TABLE 3. Comparative pharmacokinetics for S‐Methyl‐N‐N‐diethylthiocarbamate (DIS carbamate) following disulfiram 62.5 mg daily or 250 mg dailyalone or in combination with antiretroviral medications Values are the mean (standard error of the mean) for 10 subjects who participated in the study in each group.
ÃSignificantly different from the control.
to induce CYP450 enzyme activity; specifically CYP3A4.21 DIS carbamate, an intermediate in DIS metabolism, is metabolized to S‐methyl N,N‐diethylthiolcarbamate sulfoxide (DETC–MeSO) by CYP3A4, ‐2A6, and ‐2E114 and therefore, it was expected that levels of DIS carbamate would be lower in those receiving EFV as compared to those receiving DIS alone.
DETC–MeSO is the DIS metabolite responsible for ALDH Carbamate (ng/mL)
inhibition.14 The induction of CYP enzyme activity by EFV would be expected to produce increased DETC–MeSO whichwould be manifest as a relative increase in the inhibition of ALDH activity. This was observed in that ALDH activity Time (hours)
showed the greatest decrease in those receiving EFV and DISconcomitantly with a 52% decline in ALDH activity observed (baseline 363.07 [40.46] mean [SE] vs. following EFV 600 and DIS 250 mg/d: 174.75 [23.18] (p ¼ .002; shown graphically in Fig. 2). As a comparison, baseline ALDH activity in those receiving only DIS 250/d was 416.46 (71.41), which declined to 233.89 (26.14) following DIS 250 mg/d administration (44% decrease from baseline p ¼ .020). ATV and RTV were Carbamate (ng/mL)
expected to reduce the conversion of the DIS carbamate to DETC–MeSO due to their inhibition of CYP3A4.23,33 Thus, itwas expected that co would be associated with proportionately less inhibition of Time (hours)
ALDH activity relative to disulfiram alone administration.
Among subjects receiving RTV 200 and DIS 250 mg/d, FIGURE 1. Effect of antiretroviral medications on S‐methyl‐N‐N‐ baseline ALDH activity (593.17 [54.6]) significantly declined diethylthiocarbamate (DIS carbamate) at (A). Disulfiram 62.5 mg to 377.28 (42.57; 36% reduction; p ¼ .009). A non‐significant daily or (B). Disulfiram 250 mg daily.
(16%) decline in ALDH activity from 318.7 (38.91) to 266.36(39.91) was observed among subjects receiving ATV 400 mg/ This study was undertaken because the hazardous use of d with DIS 250 mg/d (shown graphically in Fig. 2). It is notable alcohol as well as alcohol use disorders are common in those that there was significant variation in individual ALDH activity with HIV infection,9–11 yet pharmacotherapies for alcohol use at baseline; therefore the proportional change in ALDH activity disorders are infrequently used in the population. This might be was used as the comparator in this study. Proportional changes largely due to the sparse evidence currently available on the in ALDH activity were consistent with the expected effect of interactions of DIS and ARV. Informing clinicians of the safety of DIS with concurrent use of ARV as well as identifying One difference observed in subjects participating in the potential problems in the use of this alcohol pharmacotherapy ATV and DIS study was an increase in total bilirubin when which has also shown promise in the treatment of cocaine ATV was administered alone or with DIS. ATV is known to dependence (4) may be helpful in increasing the clinical use ofDIS in the HIV‐infected population.
Several studies have indicated inhibitory effects of DIS treatment on CYP450 enzymatic activity (eg, CYP3A4) which are variable.20,30,31 A number of ARV are substrates of CYP3A4 including those in this study, EFV,22 ATV,32 and RTV.31 DIS was administered at two doses: 62.5 and 250 mg/d because these doses have been shown to diminish acute cocaine responses in humans.5 The finding that neither dose had a significant effect on the pharmacokinetics of any of the ALDH Activ
ARV studied suggests that DIS in clinically relevant doses can be safely used as it pertains to ARV efficacy in HIV‐infectedpeople receiving ARV therapy. Of note, the RTV formulation administered in this study was an alcohol‐containing gelcap.
No participants receiving RTV with DIS experienced Disulfiram Dose (mg/day)
symptoms of an alcohol–DIS reaction.
FIGURE 2. Effect of disulfiram in combination with antiretroviral The effect of the ARV on DIS metabolism and ALDH inhibition was consistent with study hypotheses. EFV is known Disulfiram–Antiretroviral Medication Interactions inhibit bilirubin glucuronidation by UDP glucuronosyltrans- of a DIS‐alcohol reaction. ATV administration with DIS ferase 1A1 (UGT 1A1) with a resultant increase in serum 250 mg/d was associated with only a 16% reduction in ALDH bilirubin levels that rapidly reverses on drug discontinuation.34 activity observed when these medications were administered This hyperbilirubinemia occurs without concomitant increases concomitantly. This may render DIS at standard clinical doses in transaminases and is not regarded as a sign of liver as administered in this study ineffective. Human laboratory studies that include alcohol administration following concom- One of the implications of the effect of ATV on itant administration of clinically relevant doses of the ARV and glucuronidation would be in the potential for inhibition of a DIS would be able to conclusively answer the question of DIS contributing pathway for metabolism of some DIS metabolites efficacy for alcohol dependence in those requiring ART that (diethyldithiocarbamate, for example). In humans, glucuroni- dation has been shown to be responsible for elimination of DIS has also been studied as a treatment for cocaine 1.7% of a single 250 mg dose of DIS while 8.3% of DIS is dependence. The proposed mechanism by which disulfiram eliminated by glucuronidation with chronic dosing.36 The alters cocaine responses has been postulated to be related inhibition of glucuronidation by co‐administration of ATV to inhibition of dopamine beta hydroxylase activity which might increase the amount of DIS metabolite that is subject to occurs through the disulfiram metabolite, diethyldithiocarba- CYP 450 metabolism. The inhibition of CYP 3A4 by ATV33 mate (DDTC).37 Upon oral ingestion, DIS is rapidly reduced could result in accumulation of DIS metabolites and a to its corresponding thiol, diethyldithiocarbamate (DDTC)38 concomitant decrease in the DIS metabolite responsible for and DDTC inactivates dopamine beta hydroxylase by inhibition in ALDH (DETC–MeSO). We observed a decrease chelation. Because this is the first compound formed in in ALDH inhibition by DIS when administered with ATV, but the DIS metabolic cycle; there is no expectation that the we cannot say with certainty the mechanism by which this effect of ARV on CYP 450 enzyme function would have an occurred since we were unable to measure all of the metabolites effect on this activity. If the hypothesized mechanism for formed in the DIS metabolic pathway.
DIS effect on cocaine responses is correct, then DIS would still A question arising from these results is whether DIS at be expected to be effective for treatment of cocaine use standard clinical doses used in the treatment of alcohol use disorders in those receiving ART that contained any of the disorders (ie, 250 mg/d) would be effective as a deterrent to alcohol use in those receiving antiretroviral therapies that There are limitations to this study. The number of ARV contain either EFV, RTV, or ATV. It is not possible to answer studied was limited and sample sizes were relatively small. To this question with precision because no studies have correlated address these limitations, ARV selected for study were those the proportion of reduction in ALDH activity with the expected to be likely to have interactions with DIS based on occurrence or severity of a DIS–alcohol reaction. However, their known clinical pharmacology, although there are a large in the current study there were two participants who consumed number of ARV of potential interest in terms of interactions alcohol within 3 days of discontinuation of DIS 250 mg/d (this with DIS. The study design would have benefited from an occurred following completion of study procedures). Both assay to detect DETC–MeSO and this was planned at the outset reported flushing, and one reported a sensation of labored of the study. However, the development of a reliable assay breathing while the second alcohol consumer stated that mild proved challenging leading to the use of DIS carbamate and nausea was the most prominent symptom. Each stated that they ALDH activity as surrogate markers of the effects of the ARV had started to experience these symptoms after drinking less than one glass of wine. They were told to immediately In summary, the results of drug interaction studies between discontinue alcohol use and to come for medical evaluation if three ARV that are frequently used in the treatment of HIV symptoms worsened. Both reported discontinuation of infection and DIS are reported. No effect of DIS on ARV symptoms within a few hours and neither required medical pharmacokinetics at standard therapeutic doses of medications intervention. ALDH inhibition relative to their baseline ALDH was observed, although EFV lowered DIS carbamate plasma function was determined for each of these individuals and concentrations. EFV and RTV did not interfere with the found to be 31% for one subject and 68% for the second development of significant ALDH inhibition by DIS as was participant. While inexact, it would appear that the proportion observed with ATV administration, indicating that DIS at of ALDH inhibition that occurs in an individual is related to the standard clinical doses may not be effective in deterring ability to mount a DIS–alcohol interaction with alcohol alcohol use if given concomitantly with ATV.
consumption while taking DIS. It appears, then, from theseresults that EFV would not be expected to interfere with DIS‐ This study was supported by NIDA NIH grants R01 DA mediated ALDH inhibition, nor were any adverse events 024982 (E.M.‐K.) and K24 DA 023359 (E.M.‐K.).
associated with the 8% additional ALDH inhibition observed The authors thank Vincent Samson, BA for expert technical relative to the sample receiving DIS 250 mg/d alone. RTV administration, while associated with a lesser reduction inALDH inhibition over that observed with DIS alone administration is also not likely to interfere with the occurrence Authors have no conflict of interest to declare.
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Disulfiram–Antiretroviral Medication Interactions


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