Zidovudine Atovaquone

ATOVAQUONE ANTIVIRALS-ZIDOVUDINE Atovaquone t zidovudine levels Atovaquone inhibits the glucuronidation of zidovudine Uncertain clinical significance. Monitor FBC, LFTs and lactate closely during co-administration... 

Drugs that may affect zidovudine include acetaminophen, atovaquone, bone marrow suppressive/cytotoxic agents (eg, adriamycin, dapsone), clarithromycin, doxorubicin, fluconazole, ganciclovir, methadone, nelfinavir/ritonavir, phenytoin, probenecid, ribavirin, rifamycins, stavudine, trimethoprim, and valproic acid. 

Fluconazole, probenecid and atovaquone increase the risk of myelotoxicity by zidovudine. This may be attributed to an increased plasma concentration of zidovudine in the presence of these drugs, perhaps through their inhibitory effects on glucuronose transferase. Rifabutin and rifampin decrease plasma concentrations, and clarithromycin decreases the absorption of zidovudine. Zidovudine and stavu-dine should not be used in combination because they compete for intracellular phosphorylation. 

Trapnell CB, Klecker RW, Jamis-Dow C, et al. Glucuronidation of 3 -azido-3 -deoxythymidine (zidovudine) by human liver microsomes relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and val-proic acid. Antimicrob Agents Chemother 1998 42 1592-1596. 

Lee BL, Tauber MG, Sadler B, Goldstein D, Chambers HE. Atovaquone inhibits the glucuronidation and increases the plasma concentrations of zidovudine. Clin Pharmacol Ther 1996 59(1) 14-21. 

Zidovudine glucuronidation in human hepatic micro-somes in vitro was inhibited more by the combination of fluconazole with valproic acid than with other drngs, snch as atovaquone and methadone (117). 

Atovaquone can potentiate the activity of zidovudine by inhibiting its glucuronidation (39). 

Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain terminator that is extensively glucuronidated (70% of the dose) primarily by UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir, tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone (McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7 substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate (Lertora, 1994). Rifampin increased the formation clearance to AZT-glucuronide by twofold (Gallicano, 1999). 

Moderate increases in the AUC of zidovudine, not usually requiring dose adjustments, have been seen with atovaquone. However, it may be prudent to regularly monitor for adverse effects. Atovaquone decreased the AUC of didanosine. Neither didanosine nor zidovudine affected atovaquone pharmacokinetics. 

A study in 14 HIV-positive patients given atovaquone 750 mg every 12 hours and zidovudine 200 mg every 8 hours found that under steady-state conditions the zidovudine had no effect on the pharmacokinetics of atovaquone. This confirmed the findings of a previous analysis of pharmacokinetic data from a small number of patients enrolled in clinical studies. However, the AUC of the zidovudine was increased by about 30%, and its clearance was reduced by 25% by the concurrent use of atovaquone. ... 

Atovaquone might inhibit the metabolism (glucuronidation) of zidovudine. ... 

The manufacturer of atovaquone notes that the decrease in didanosine levels is unlikely to be clinically relevant. They also say that the increased plasma levels of zidovudine likely with a 3-week course of atovaquone for acute Pneumocystis pneumonia are unlikely to increase the adverse effects of zidovudine, and routine dose adjustments are not required. Nevertheless, the manufacturers of atovaquone and zidovudine do recommend reg-... 

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