Zidovudine is a widely used antiretroviral drug active against human immunodeficiency virus. The drug interactions of this compound, which are primarily eliminated as a glucuronide, have not yet been extensively studied. Because zidovudine is frequently combined with other drugs, complete knowledge of interactions is essential to optimize AIDS therapy. We therefore screened the effect of 55 molecules, representative of 20 different therapeutic classes, on 3´-azido-3´-deoxythymidine (AZT) glucuronidation by human liver microsomes. We demonstrate that many drugs caused more than 15% inhibition of AZT glucuronidation in vitro, whereas major antibiotics (ceftazidine, isoniazid, aminoglycosides, macrolides, and sulfamides), antivirals (2´,3´-dideoxycytidine, 2´,3´-dideoxyinosine, and acyclovir), flucytosine, metronidazole, acetaminophen, and ranitidine had no effect. For compounds that appeared to inhibit AZT glucuronidation, extrapolation to the clinical situation must take into account both the in vitro apparent Ki values and the usual expected plasma level for the coadministered drug. By considering these parameters, this work indicates that clinically relevant inhibition of AZT glucuronidation may be observed with the following drugs: cefoperazone, penicillin G, amoxicilin, piperacillin, chloramphenicol, vancomycin, miconazole, rifampicin, phenobarbital, carbamazepine, phenytoin, valproic acid, quinidine, phenylbutazone, ketoprofen, probenecid, and propofol. Complementary clinical and pharmacokinetic studies should be performed to validate these assumptions

OBJECTIVE: To determine whether concurrent treatment with acetaminophen and zidovudine impairs clearance of zidovudine, thereby increasing the risk for zidovudine-induced hematologic toxicity. DESIGN: Dose escalation, drug interaction study. SETTING: University clinical research center. PATIENTS: Patients with the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex. INTERVENTIONS: Acetaminophen and 200 mg of zidovudine simultaneously every 4 hours. For 13 patients, the unit dosage of acetaminophen was 325 mg for 3 days; for 8 patients, the dosage was 650 mg for 3 days; and, for 6 patients, the dosage was 650 mg for 7 days. MEASUREMENTS: Zidovudine clearance and production of the glucuronide conjugate of zidovudine were assessed after acetaminophen treatment. MAIN RESULTS: Neither zidovudine clearance nor production of the glucuronide conjugate of zidovudine was impaired after treatment with acetaminophen. Clearance of zidovudine was actually accelerated by 5%, 11%, and 33% with the three acetaminophen regimens, respectively (P = 0.002 by analysis of variance; P = 0.04 for linear trend when changes in the area-under-the-curve for zidovudine were compared). CONCLUSION: Because serum concentrations of zidovudine decrease after the coadministration of acetaminophen, a pharmacokinetic interaction between zidovudine and acetaminophen is unlikely to increase the risk for hematologic toxicity associated with zidovudine

The glucuronidation of 3´-azido-3´-deoxythymidine (AZT) by human liver microsomes and human hepatocytes in culture has been studied in vitro to determine the UDP-glucuronosyltransferase (UDPGT) form conceivably involved in the AZT biotransformation process. The glucuronide of AZT was preliminarily identified through hydrolysis by beta-D-glucuronidase. Brij 58 was shown to be the best activator of AZT glucuronidation by human liver microsomes, as it increased the rate of glucuronide formation 3-fold. The UDPGT activities toward AZT measured in 29 different microsomal fractions was slightly variable among samples (79 to 268 nmol/hr/mg protein). The apparent KM value for AZT glucuronidation was about 5 mM. We sought to determine if various known UDPGT activities (i.e. p-nitrophenol UDPGT, 4-hydroxybiphenyl UDPGT, and DT1-UDPGT) in 18 microsomal samples were correlated with AZT-UDPGT activity. Experiments revealed that only 4-hydroxybiphenyl UDPGT activity was strongly correlated (r = 0.815, p less than 0.001) with AZT-UDPGT activity, whereas no correlation was found for the other UDPGT activities. To determine the isozyme conceivably involved in AZT glucuronidation, we studied the effect of various compounds on AZT glucuronidation. AZT glucuronidation was inhibited by numerous substrates of the UDPGT2, form: morphine (Ki = 1.8 mM), 4-hydroxybiphenyl (Ki = 0.92 mM), and ketoprofen (Ki = 0.75 mM), but also oxazepam, codeine, and chloramphenicol. p-Nitrophenol appeared to be an inhibitor, whereas acetaminophen had no effect. Bilirubin, aspirin, cimetidine, and acyclovir did not inhibit AZT glucuronidation. Since all the inhibitors tested except p-nitrophenol are known to be glucuronidated by the UDPGT2 form, our results strongly suggest the involvement of this isozyme in AZT glucuronidation.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the development of severe hepatotoxicity in a patient on zidovudine therapy who received 3.3 g of acetaminophen in less than 36 hours. Three days later, the patient's serum aspartate aminotransferase level was 5,724 U/L, alanine aminotransferase was 3,124 U/L, lactate dehydrogenase was 12,675 U/L, alkaline phosphatase was 84 U/L, and total bilirubin was 20 mumol/L. These values substantially improved over the ensuing 4 days. Serologic results for hepatitis B, hepatitis A, and cytomegalovirus were all negative. The pattern and time sequence of transaminase elevation in this patient are consistent with acute acetaminophen hepatotoxicity, especially since zidovudine-induced hepatotoxicity is described as producing cholestasis rather than acute hepatitis. We hypothesize that our patient's susceptibility to acetaminophen-dependent hepatotoxicity may have been augmented by competitive utilization of glucuronidation by other drugs such as zidovudine and/or trimethoprim-sulfamethoxazole with subsequent increased cytochrome P450-dependent metabolism of acetaminophen. Additionally, due to malnutrition and/or to human immunodeficiency virus infection per se, our patient may have had decreased hepatic reserves of glutathione with which to conjugate the toxic acetaminophen product of the P450 system. Although severe acetaminophen-associated hepatotoxicity has not previously been reported in patients receiving zidovudine, we suggest that clinicians be aware of this potential interaction and counsel malnourished patients, especially those with concomitant hepatic disease, to exercise caution when taking both these medications

OBJECTIVE: To investigate a possible pharmacokinetic interaction between zidovudine and paracetamol. METHODS: Six patients with AIDS took both zidovudine (AZT; 1000-1200 mg/day) and paracetamol (500 mg every 6 h) for 7 days. Pharmacokinetic monitoring was performed on day 0 (AZT alone) and after 7 days of combined use of paracetamol and AZT. RESULTS: Combined use of paracetamol and AZT did not result in a significant change in any of the calculated pharmacokinetic parameters of AZT or its primary metabolite AZT-glucuronide. In addition, paracetamol pharmacokinetic parameters at day 7 did not differ from those usually reported in the literature. CONCLUSION: Short-term, combined use of paracetamol and AZT does not lead to a change in the pharmacokinetics of either AZT or paracetamol. The effect of long-term use of this combination remains unknown. A recent case report of AZT-induced paracetamol hepatotoxicity [Am J Med 1992;93: 94-96] indicates that clinicians should still be aware of potential drug toxicity when prescribing both AZT and paracetamol

The concomitant administration of acetaminophen to HIV-positive patients receiving zidovudine (AZT) therapy has previously been thought to increase the likelihood of the toxicity of AZT due to increased serum levels, resulting from hypothesized metabolic competition. We measured serum AZT and metabolite levels by HPLC in HIV-infected patients taking regular doses of AZT with and without acetaminophen administration. In all patients, serum levels of AZT and the glucuronidated metabolite (GAZT) were similar with and without acetaminophen administration. AZT serum levels were not increased (p less than 0.05). We believe that the rationale for withholding acetaminophen from patients receiving AZT should be re-evaluated

1. Zidovudine (3´-azido-3´-deoxythymidine; AZT) is the drug of proven efficacy available for the treatment of patients with AIDS or ARC. It is eliminated mainly by hepatic glucuronidation. Therefore, interference with this metabolic pathway may lead to enhancement of AZT effect or to increased toxicity of the drug. We have examined the effect of a number of drugs which themselves undergo glucuronidation on AZT conjugation by human liver microsomes in vitro. 2. AZT glucuronidation followed Michaelis-Menten kinetics. The apparent Km and Vmax values (mean +/- s.d., n = 5), were 2.60 +/- 0.52 mM and 68.0 +/- 23.4 nmol h-1 mg-1, respectively, as determined from Eadie-Hofstee plots. 3. Dideoxyinosine, sulphanilamide and paracetamol were essentially non-inhibitory at concentrations up to 10 mM (4 times the concentration of AZT in the incubation). The most marked inhibitory effects were seen with indomethacin, naproxen, chloramphenicol, probenecid and ethinyloestradiol, with enzyme activity decreased by 97.7, 94.9, 88.7, 83.4% and 79.0%, respectively, at a concentration of 10 mM. Other compounds producing some inhibition of AZT conjugation were oxazepam, salicylic acid and acetylsalicylic acid. 4. Further studies are necessary to characterise the inhibition observed but the method described enables a screen of potentially important drug interactions to be carried out