PHARMACEUTICAL PROPERTIES OF RELATED CALANOLIDE COMPOUNDS WITH ACTIVITY AGAINST HUMAN-IMMUNODEFICIENCY-VIRUS

The present studies were undertaken to compare the relative pharmacoki netic parameters and bioavailability of two chemically related natural products which are nonnucleoside inhibitors of reverse transcriptase. Both (+)-calanolide A (Cal A; NSC 675451) and (+)-dihydrocalanolide A (DHCal A; NSC 678323) are currently under development for the treatme nt of HIV infections. HPLC-based analytical assays were developed for both compounds using modifications of a previously published procedure . The assays were used to compare the intravenous pharmacokinetics of the dihydro analogue relative to the parent compound, Cal A, and to de termine the relative oral bioavailability of each drug in CD2F1 mice. Although the pharmacokinetic parameters of each drug were similar (Cal A, 25 mg/kg: AUC: 9.4 [mu g/mL].hr, t(1/2)beta: 0.25 h,, t(1/2)gamma: 1.8 h, clearance: 2.7 L/h/kg versus DHCal A, 25 mg/kg, AUC: 6.9 [mu g /ml].hr, t(1/2)beta: 0.22 h,, t(1/2)gamma: 2.3 h, clearance: 3.6 L/h/k g), the oral bioavailability of DHCal A (F = 46.8%) was markedly bette r than that obtained for Cat A (F = 13.2%). The relative ability of Ca l A and DHCal A to change to their inactive epimer forms, (+)-calanoli de B and (+)-dihydrocalanolide B, respectively, was also determined. W hile conversion of active to inactive forms of the drugs was noted to occur in vitro especially under acidic conditions, no epimer forms of either compound were noted in plasma of mice after administration of e ither CalA or DHCal A. Considered together with preliminary toxicology findings, the pharmacokinetic data obtained in the present series of experiments suggest that selection of the dihydro derivative of (+)-ca lanolide A may be a reasonable choice for further preclinical developm ent and possible Phase I clinical evaluation.