EFFECT OF METOCLOPRAMIDE AND LOPERAMIDE ON THE PHARMACOKINETICS OF DIDANOSINE IN HIV-SEROPOSITIVE ASYMPTOMATIC MALE AND FEMALE-PATIENTS

The pharmacokinetics of orally-administered didanosine were evaluated in 6 male and 6 female HIV seropositive patients to determine the effe ct of pretreatment with metoclopramide, an inducer of gastrointestinal motility, and loperamide, which retards motility. Using a randomized, balanced, crossover design, each patient received the following three treatments under fasting conditions: didanosine as a single agent, di danosine 5 min after a single 10 mg intravenous dose of metoclopramide , and didanosine 1 h after the final of 4 doses, 4 mg each, of loperam ide. Serial blood and urine samples were collected for up to 12 h afte r each dose. Plasma and urine aliquots were analysed for intact didano sine using HPLC with UV detection. Pharmacokinetic parameter values we re calculated using noncompartmental methods. The mean C(max) values w ere significantly greater for the didanosine single agent (2.04 mug . ml-1) and didanosine with metoclopramide (2.30 mug . ml-1) treatments than for the combination of didanosine with loperamide (1.57 mug . ml- 1). The t1/2 in males was significantly greater than in females for th e didanosine (1.75 vs 1.12 h, respectively) and didanosine with metocl opramide treatments (1.74 vs 1.20 h, respectively). No significant tre atment or gender effects were observed for AUC or UR (urinary recovery ). The pharmacokinetics of didanosine were not altered appreciably by dosing with metoclopramide. Administration with loperamide affected th e rate but not the extent of absorption. There were no clinically rele vant differences between males and females in the disposition of didan osine.