Zalcitabine Probenecid

Drugs that may affect valganciclovir include didanosine, imipenem-cilastin, nephrotoxic drugs, probenecid, trimethoprim, zalcitabine, and zidovudine. Drugs that may be affected by valganciclovir include cytotoxic drugs, didanosine, and zidovudine. 

Drugs that may interact with zalcitabine include antacids, chloramphenicol, cisplatin, dapsone, didanosine, disulfiram, ethionamide, glutethimide, gold, hydralazine, iodoquinol, isoniazid, metronidazole, nitrofurantoin, phenytoin, ribavirin, vincristine, cimetidine, metoclopramide, amphotericin, aminoglycosides, foscarnet, antiretroviral nucleoside analogs, pentamidine, and probenecid. 

Potential drug interactions include an increased AUC of zalcitabine when administered in combination with probenecid or cimetidine and decreased bioavailability when zalcitabine is coadministered with antacids or metoclopramide. Lamivudine inhibits the phosphorylation of zalcitabine in vitro, potentially interfering with its efficacy. 

Lamivudine inhibits the intracellular phosphorylation of zalcitabine and antagonizes zalcitabine s antiretroviral activity in vitro, although the clinical significance of this interaction is unknown. Probenecid increases the zalcitabine AUC by about 50%, probably through inhibition of tubular secretion cimetidine increases the AUC by 36% via an unknown mechanism. Zalcitabine should be avoided in patients with a history of pancreatitis or neuropathy because the risk and severity of both complications increase. Coadministration of other drugs that cause pancreatitis or neuropathy also will increase the risk and severity of these symptoms. Ethambutol, isoniazid, vincristine, cisplatin, and pentamidine, as well as the antiretroviral drugs didanosine and stavudine, therefore, should be avoided. 

Zidovudine and probably other cytotoxic agents increase the risk of myelosuppression, as do nephrotoxic drugs that impair ganciclovir excretion. Probenecid and possibly acyclovir reduce renal clearance of ganciclovir. Zalcitabine increases oral ganciclovir exposure by -22%. Oral ganciclovir doubles the absorption and peak plasma concentrations of didanosine and increases zidovudine by -20%. 

Probenecid reduces the loss of zalcitabine and zidovudine, increasing their serum levels. The combination of zalcitabine and probenecid is well tolerated, but the incidence of adverse effects appears to be greatly increased with the combination of probenecid and zidovudine. 

In a single-dose study, 12 HIV-positive or AIDS patients were given zalcitabine 1.5 mg alone or with probeneeid 500 mg, given 8 and 2 hours before then 4 hours after. The renal clearance of the zalcitabine was decreased 42% by probenecid, its half-life was increased by 47% and its AUC was increased by 54%. ... 

Experimental clinical evidence indicates that probenecid reduces metabolism (glucuronidation) of zidovudine by the liver enzymes, and inhibits renal secretion of the zidovudine glucuronide metabolite. " " The interaction with zalcitabine is presumably due to inhibition of zalcitabine secretion in the renal tubules. ... 

The concurrent use of zalcitabine and probenecid was well tolerated, and because the zalcitabine half-life is short compared to its dosing schedule significant accumulation would not be expected. 

Massarella JW, Nazareno LA, Passe S, MinB. The effect of probenecid the Jiarmacoki-netics of zalcitabine in HIV-positive patients. PharmRes (19 13,449-52. 

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