Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases.
We investigated the clinical pharmacokinetics of azidothymidine (N3TdR) as part of a phase I/II trial in the treatment of acquired immunodeficiency syndrome and related diseases. During the 6-week course of therapy, drug levels in plasma, cerebrospinal fluid, and urine were determined by HLPC. The plasma half-life of N3TdR was 1.1 hour. The total body clearance was 1.3 L/kg/hr. At intravenous doses of 5 mg/kg or oral doses of 10 mg/kg, plasma levels were continuously maintained above the target level of 1 mumol/L. Oral bioavailability was 63% +/- 13%. Substantial penetration of N3TdR into cerebrospinal fluid was demonstrated. At doses of 5 mg/kg intravenously or 10 mg/kg orally, cerebrospinal fluid drug levels exceeded and were maintained close to 1 mumol/L. Nineteen percent of the administered dose was excreted unchanged into the urine. Renal clearance was 0.23 L/kg/hr. N3TdR possesses pharmacokinetic properties that would facilitate the long-term treatment of patients with acquired immunodeficiency syndrome: it can be given orally and it penetrates the central nervous system.
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000378:metabolism*; D000284:Administration, Oral; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D002986:Clinical Trials as Topic; D004341:Drug Evaluation; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007700:Kinetics; D013936:Thymidine / Q000031:analogs & derivatives* / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000627:therapeutic use; D015215:Zidovudine
D015215:Zidovudine; D013936:Thymidine