Zidovudine Fluconazole

KJ is a 45-year-old woman currently on the following medications nelfinavir, lamivudine, zidovudine, fluconazole (prophylaxis for thrush), and TMP-SMX. Which of the following two agents are most likely to be causing her anemia ... 

Drugs that may affect fluconazole include cimetidine, hydrochlorothiazide, and rifampin. Drugs that may be affected by fluconazole include alfentanil, benzodiazepines, buspirone, carbamazepine, cisapride, oral contraceptives, corticosteroids, cyclosporine, haloperidol, HMG-CoA reductase inhibitors, losartan, nisoldipine, phenytoin, protease inhibitors, rifabutin, sirolimus, sulfonylureas, tacrolimus, theophylline, tolterodine, tricyclic antidepressants, vinca alkaloids, warfarin, zidovudine, and zolpidem. 

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. 

Fluconazole Fluconazole may increase the plasma concentration of phenytoin, sulfonylurea (hypoglycemic), cyclosporin, zidovudine, cisapride, and terfenadine. Coadministration of fluconazole with rifampicin results in the reduced plasma concentration of fluconazole. Griseofulvin may reduce the plasma concentration of salicylates, coumarin, anticoagulants, and oral contraceptives. 

FLUCONAZOLE ZIDOVUDINE t zidovudine levels Inhibition of metabolism Avoid co-administration... 

A 35-year old Caucasian man with AIDS and multiple opportunistic infections, including Mycobacterium kansasii and Mycobacterium avium complex (MAC) disease developed moderate to severe primary sensorineural hearing loss after 4—5 months of therapy with oral azithromycin 500 mg/day. Other medications included ethambutol, isoniazid, rifabutin, ciprofloxacin, co-trimoxazole, fluconazole, zidovudine (later switched to stavudine), lamivudine, indinavir, methadone, mod-ified-release oral morphine, pseudoephedrine, diphenhydramine, megestrol acetate, trazodone, sorbitol, salbutamol by metered-dose inhaler and nebulizer, ipratropium, and oral morphine solution as needed. Significant improvement of the hearing impairment was documented 3 weeks after drug withdrawal. 

Because efavirenz is metabolized by cytochrome P450, several clinically significant interactions have been described. Efavirenz induces CYP3A4 (5) there was 55% mean induction at a dose of 400 mg/day and 33% at 200 mg/day. However, no significant interaction was noted with co-administration of nelfinavir, zidovudine, lamivudine, fluconazole, or azithromycin (2). 

In one study in patients with AIDS taking prophylactic maintenance fluconazole for cryptococcal meningitis, there was a higher rate of hematological toxicity with fluconazole than with placebo, but this probably reflected the greater proportional and absolute amounts of zidovudine used in the fluconazole group there was no serious hematotoxicity (SED-12, 682). 

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). 

B Zidovudine and TMP-SMX are both known to suppress bone marrow and cause anemia. Nelfinavir, lamivudine, and fluconazole are not usually known to cause anemia. 

Items 6-7 A patient with AIDS has a CD4 count of 45/ xL. He is being maintained on a three-drug regimen of indinavir, zalcitabine, and zidovudine. For prophylaxis against opportunistic infections, he is also receiving cidofovir, fluconazole, rifabutin, and trimethoprim-sulfamethoxazole. 

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). 

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