EFFECT OF FLUCONAZOLE ON PHARMACOKINETICS OF 2',3'-DIDEOXYINOSINE IN PERSONS SEROPOSITIVE FOR HUMAN-IMMUNODEFICIENCY-VIRUS

Fluconazole inhibits cytochrome P-450-mediated enzymatic metabolism of several drugs. Since hepatic metabolism is partially responsible for 2',3'-dideoxyinosine (didanosine or ddl) elimination, fluconazole ther apy may lead to increased ddI concentrations in serum and subsequent c oncentration-dependent adverse effects. The purpose of this study was to determine if ddI pharmacokinetics are influenced by a 7-day course of oral fluconazole. Twelve adults with human immunodeficiency virus ( HIV) who had received a constant dosage of ddI for at least 2 weeks we re investigated. On study day 1, multiple serum samples for determinat ion of ddI concentrations were obtained over 12 h. Then subjects recei ved a 7-day course of oral fluconazole (200 mg every 12 h for two dose s and then 200 mg once daily for 6 days) while ddI therapy continued. Following the last dose of fluconazole, serum samples for determinatio n of ddI concentrations Here again obtained over 12 h, ddI concentrati ons in serum were analyzed by radioimmunoassay. In contrast to previou sly published data, there was marked between-subject variability in dd I areas under the concentration-time curve, even when the dose was nor malized for weight. No significant differences were found between mean ddI areas under the concentration-time curve from 0 to 12 h on study day 1 (1,528 +/- 902 ng . hr/ml) and following fluconazole treatment ( 1,486 +/- 649 ng . hr/ml). There were no significant differences in ot her pharmacokinetic parameters, such as ddI peak concentrations in ser um (971 +/- 509 and 942 +/- 442 ng/ml) or half-lives (80 +/- 32 and 85 +/- 21 min.) before and after fluconazole treatment, respectively. We conclude that a 7-day course of oral fluconazole does not significant ly alter ddI pharmacokinetics in adults that are infected with human i mmunodeficiency virus.