Pharmacokinetics of zidovudine and dideoxyinosine alone and in combination in patients with the acquired immunodeficiency syndrome.
1. Zidovudine (ZDV) has proved unsuccessful in controlling disease progression over extended periods of time in patients with AIDS. Combination of ZDV with another reverse transcriptase inhibitor, dideoxyinosine (ddI) may improve the duration of effectiveness of antiretroviral therapy. The aim of this study was to investigate the possibility of a pharmacokinetic drug interaction between ZDV and ddI. 2. The pharmacokinetics of ZDV and ddI were determined in eight patients with AIDS who were randomised to receive ZDV 250 mg orally, ddI 250 mg orally or a combination of ZDV 250 mg plus ddI 250 mg orally on 3 study days separated by 1 week. 3. The administration of ZDV did not significantly alter ddI pharmacokinetics. The mean AUC was 6.8 +/- 2.0 s.d. and 7.6 +/- 2.5 s.d. mumol l-1 h and oral clearance was 2766 +/- 686 and 2660 +/- 1297 ml min-1 in the presence and absence of ZDV, respectively. 4. In the presence of ddI the elimination half-life of ZDV was increased significantly by 18% from 1.1 +/- 0.3 to 1.3 +/- 0.3 h (P < 0.05) and the mean AUC increased significantly by 35% from 4.8 +/- 1.5 to 6.5 +/- 1.5 mumol l-1 h (P < 0.05). The clearance was decreased by 29% from 3518 +/- 1123 to 2505 +/- 575 ml min-1, but this difference was not significant. The renal clearance of ZDV was not altered by ddI. 5. Administration of ddI also resulted in a significant 22% increase in the AUC of GZDV, from 28.5 +/- 15.7 to 34.9 +/- 12.8 mumol l-1 h (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Barry
M
M
Department of Pharmacology and Therapeutics, University of Liverpool.
Howe
J L
JL
Ormesher
S
S
Back
D J
DJ
Breckenridge
A M
AM
Bergin
C
C
Mulcahy
F
F
Beeching
N
N
Nye
F
F
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015215:Zidovudine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine
D015215:Zidovudine; C055886:3'-azido-3'-deoxy-5'-O-beta-glucopyranuronosylthymidine; D016049:Didanosine