Pharmacokinetics of Anti‐HIV Nucleosides in Microswine

Abstract— The objective of the study was to determine if the micropig (Sus scrofa) would serve as an animal model for the anti‐HIV nucleosides 3′‐azido‐3′‐deoxythymidine (AZT), 2′,3′‐dideoxyinosine (ddI), and 2′,3′‐dideoxycytidine (ddC). Four adult male micropigs were administered i.v. 20 mg kg⁻¹ AZT, 20 mg kg⁻¹ ddI, both as 10 min infusions, and 5 mg kg⁻¹ ddC, as an i.v. bolus. At least 12 days separated each drug administration. Following each drug administration, blood samples were collected by venipuncture and urine was collected by placement of the animals in metabolism cages. Concentrations of parent drug and AZT's glucuronide metabolite were quantitated in plasma and urine by HPLC. Data were analysed by non‐compartmental methods to obtain pharmacokinetic parameters for each drug. Total and renal clearances for AZT, 0·482 ± 0 058 and 0·326±0·075 L h⁻¹ kg⁻¹, respectively, and for ddI, 0·500±0057 and 0·337 ± 0·100 L h⁻¹ kg⁻¹, showed that these drugs were eliminated primarily by renal excretion rather than by liver metabolism as in man. ddC's clearances were similar to rates in man. Volume of distribution at steady state values were 0·784 ± 0·071, 1·192±0·288 and 0·886±0·199 L kg⁻¹ for AZT, ddI and ddC, respectively. Half‐life values for AZT, ddI and ddC were 1·39±0·127, 2·585 ± 0·243 and 1·832 ± 0·380 h, respectively. Based on these findings, the micropig could be an appropriate model for the study of ddC in man, but not for AZT of ddI. 1991 Royal Pharmaceutical Society of Great Britain