PHARMACOKINETIC EVALUATION OF ANTI-HIV DRUG-INTERACTIONS - EFFECT OF ZIDOVUDINE ON 2'-3'-DIDEOXYINOSINE KINETICS IN MONKEYS

The current investigation was conducted to determine if zidovudine (AZ T) altered the pharmacokinetics of dideoxyinosine (ddl) in non-human p rimates, an appropriate animal model for AZT and ddl pharmacokinetics in human. Each of nine animals received 20 mg kg-1 of ddl intravenousl y in the absence and presence of two different dosage regimens of AZT. For each combination regimen, AZT was administered as a combined i.v. bolus-constant rate infusion regimen for 30 min that produced AZT pla sma concentrations of about 4 mug ml 1 in six animals (low dose group) and 11 mug ml-1 in three others (high dose group). Serial blood sampl es were collected, and pharmacokinetic parameters for ddl were calcula ted based on plasma ddl concentrations measured by HPLC techniques. Th e pharmacokinetics of ddl given alone in the first phase of the low (n = 6) and high (n = 6) dose AZT groups, resulted in a mean elimination half-life 1.54 and 1.9h, a mean total clearance of 0.62 and 0.731 h-1 kg-1, and a mean steady state volume of distribution of 1.02 and 0.89 1 kg-1, respectively. Following combined ddl and AZT administrations, in both the low and high dose AZT groups, plasma concentration-time pr ofiles of ddl were similar for each monkey, and no statistical differe nces were observed in the pharmacokinetic parameters compared to those obtained when ddl was given alone. The fact that AZT does not alter t he pharmacokinetics of ddl at the range of AZT dose studied provides a basis for rational dosage design for combined ddl and AZT treatments in HIV infection.