Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
ZIDOVUDINE PHARMACOKINETICS AND INTERACTION STUDIES WITH PROBENECID
Diss Abstr Int [B]; 50(8):3422 1990. Unique Identifier : AIDSLINE ICDB/90665058 Hedaya MA; Univ. of Minnesota
Abstract:
Zidovudine (AZT) is currently the only antiviral drug approved for the treatment of acquired immunodeficiency syndrome (AIDS). In patients, this agent is rapidly eliminated from the body with a terminal half-life of less than 2 hr following oral dosing. Thus, frequent administration of AZT is necessary to maintain effective plasma concentrations. The pharmacokinetic drug interaction between probenecid and AZT was studied as a possible means of slowing the metabolic and renal elimination of AZT. Probenecid coadministration resulted in inhibition of both metabolism and renal excretion of this antiviral drug in the rabbit. This was reflected by higher average AZT plasma concentrations during probenecid treatment when compared with control. This interaction may allow for less frequent oral dosing, resulting in a reduction of the daily dosage requirements of AZT. The distribution of antiviral drugs into the central nervous system (CNS) is very important for the treatment of the neurological complications associated with AIDS. The effect of probenecid on the distribution of AZT into the cerebrospinal fluid (CSF) was studied in the rabbit. Probenecid coadministration resulted in an increase in the CSF/plasma concentration ratio at steady state during continuous intravenous administration of AZT. Also, the average CSF/plasma concentration ratio after a single intravenous dose of AZT was increased during probenecid coadministration. Pharmacokinetic analysis of the results suggested that the enhanced distribution of AZT into the rabbit CSF caused by probenecid was due in part to inhibition of the CSF to plasma active transport. The effect of probenecid on the metabolic and renal clearances of AZT was examined in two normal volunteers in a balanced crossover study. Probenecid coadministration resulted in a decrease in both metabolic and renal clearances of AZT. Modification of the transport of AZT across the CSF/plasma barrier may facilitate distribution of AZT into the CNS, an extremely desirable goal in treating AIDS dementia complex. A decrease in AZT clearance resulting from probenecid coadministration may reduce the daily dosage requirements of AZT and therefore have a significant impact on the cost of therapy of patients with AIDS or AIDS related complex. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD90-01017)
Keywords: Animal AIDS Dementia Complex/DRUG THERAPY Brain/METABOLISM Drug Interactions Human Kidney/METABOLISM Metabolic Clearance Rate Probenecid/*PHARMACOLOGY Rabbits Zidovudine/BLOOD/CEREBROSPINAL FLUID/*PHARMACOKINETICS/ THERAPEUTIC USE THESIS 900630
M9060634
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Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
