Pharmacokinetics and bioavailability of zidovudine in humans.
The basic pharmacokinetic and bioavailability information on zidovudine was obtained during the initial phase I study. Following intravenous doses of 1.0 mg/kg every eight hours to 7.5 mg/kg every four hours, zidovudine plasma levels decay in a biexponential manner, indicating two-compartment pharmacokinetics. The mean half-life was 1.1 hours over this dose range and the total body clearance was approximately 1,900 ml/minute/70 kg, up to doses of 5 mg/kg. At 7.5 mg/kg, total body clearance decreased by 35 percent. The 5'-O-glucuronide was identified as a major metabolite of zidovudine in plasma and urine. This inactive metabolite is rapidly formed and cleared from plasma, with a half-life of one hour. No other metabolites have been found in humans. Renal clearance of zidovudine was estimated at 350 ml/minute/70 kg. Zidovudine penetrated the blood brain barrier as indicated by a cerebrospinal fluid:plasma ratio averaging 0.5, determined two to four hours after dosing. Following oral administration of zidovudine at doses from 2.0 mg/kg every eight hours to 10 mg/kg every four hours, peak plasma levels increased proportionately with dose; the average bioavailability was 65 percent. Since 90 percent of the drug was recovered in the urine as zidovudine or the 5'-O-glucuronide, the incomplete bioavailability is assumed to be the result of first-pass metabolism rather than incomplete absorption. Pharmacokinetic questions related to optimal use of the drug are currently being addressed.
Blum
M R
MR
Department of Medical Biochemistry, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Liao
S H
SH
Good
S S
SS
de Miranda
P
P
D000386:AIDS-Related Complex / Q000188:drug therapy*; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D004341:Drug Evaluation; D006801:Humans; D013936:Thymidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015215:Zidovudine
D000998:Antiviral Agents; D015215:Zidovudine; D013936:Thymidine