PHARMACOKINETICS AND BIOAVAILABILITY OF ZIDOVUDINE AND ITS GLUCURONIDATED METABOLITE IN PATIENTS WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION AND HEPATIC-DISEASE (AIDS CLINICAL-TRIALS GROUP PROTOCOL-062)

The pharmacokinetics of zidovudine (ZDV) are established in patients w ith various stages of human immunodeficiency virus (HN) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease, HIV-in fected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as m ild), Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on th e second day, Blood samples were obtained over an 8-h collection inter val, and concentrations of ZDV and its glucuronidated metabolite (GZDV ) were determined by high-performance liquid chromatography. The follo wing pharmacokinetic parameters were obtained after oral administratio n of ZDV to HIV-infected patients with mild hepatic disease; these val ues were compared with previously reported data in healthy volunteers, The area under the curve (AUG) (1,670 +/- 192 ng . h/ml), maximum con centration of drug in serum (1,751 +/- 180 ng/ml), and half-life (2.04 +/- 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 +/- 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 +/ - 1,222 ng . h/ml) and maximum concentration of drug in serum (5,220 /- 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2.79 +/- 0.4 3) after oral administration were decreased, ZDV absolute bioavailabil ity was 0.75 +/- 0.15 in HIV-infected patients with mild hepatic disea se, Although the ZDV apparent oral clearance was not impaired as signi ficantly as in patients with biopsy-proven cirrhosis, our results sugg est that ZDV could accumulate in HIV-infected patients,vith mild hepat ic disease because of impaired formation of GZDV, Patients with mild h epatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy,