Probenecid reduces loss of zalcitabine and zidovudine, increasing their serum levels. The combination of zalcitabine andprobenecid is well tolerated, but incidence of adverse effectsappears to be greatly increased with combination of probenecid and zidovudine.
In a single-dose study,12 HIV-positive or AIDS patients were given zalcitabine 1.5mg alone or with probenecid 500 mg,given 8 and 2 hrs before then 4 hrs after. The renal clearance of zalcitabine was decreased 42 % by probenecid, its half-life was increased by 47 % and its AUC was increased by 54 % (See reference number 1).
In 12 patients with AIDS or AIDS-related complex concurrent use of zidovudine and probenecid 500mg every 8 hrs for 3 days increased AUC of zidovudine by an average of 80 % (range 14 to 192%) (See reference number 2)
Other studies in patients(See reference number 3-5) and healthy subjects(See reference number 6) found that probenecid roughly doubled AUC of zidovudine when given in a variety of dosing schedules (See reference number 3,4). However, effects on zidovudine pharmacokinetics were minimal if two drugs were given 6 hrs apart (See reference number 5). Another report describes a very high incidence of rashes in 6 out of 8 HIV-positive men given zidovudine with probenecid 500mg every 6 hours. The rash and other symptoms (such as malaise, fever and myalgia) were sufficiently severe for probenecid to be withdrawn in 4 of them (See reference number 7). A later study found that when using only 250mg of probenecid every 8 hrs AUC of zidovudine was increased by 70 % but adverse effects still occurred, although incidence was possibly somewhat lower (See reference number 8). Conversely, others reported successful use of probenecid 500mg three times daily with a reduced dose of zidovudine (600 mg daily) in 7 patients without any occurrence of rash (See reference number 9).
Experimental clinical evidence indicates that probenecid reduces metabolism (glucuronidation) of zidovudine by liver enzymes, and inhibits renal secretion of zidovudine glucuronide metabolite (See reference number 2-4,6,10,11). The interaction with zalcitabine is presumably due to inhibition of zalcitabine secretion in renal tubules (See reference number 1).
The concurrent use of zidovudine and probenecid should be well monitored to ensure that zidovudine levels do not rise excessively. Reduce zidovudine dosage as necessary. However, apparent increase in adverse effects during concurrent use seen by one group of researchers(See reference number 7,8)should be borne in mind.
The concurrent use of zalcitabine and probenecid was well tolerated, and because zalcitabine half-life is short compared to its dosing schedule significant accumulation would not be expected.
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