Pharmaceutical properties of related calanolide compounds with activity against human immunodeficiency virus.
The present studies were undertaken to compare the relative pharmacokinetic 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 treatment 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 determine 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 [microg/mL]. hr, t1/2beta: 0.25 h,, t1/2gamma: 1.8 h, clearance: 2.7 L/h/kg versus DHCal A, 25 mg/kg: AUC: 6.9 [microg/mL].hr, t1/2beta: 0.22 h,, t1/2gamma: 2.3 h, clearance: 3.6 L/h/kg), the oral bioavailability of DHCal A (F = 46. 8%) was markedly better than that obtained for Cal A (F = 13.2%). The relative ability of Cal A and DHCal A to change to their inactive epimer forms, (+)-calanolide B and (+)-dihydrocalanolide B, respectively, was also determined. While 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 either 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 (+)-calanolide A may be a reasonable choice for further preclinical development and possible Phase I clinical evaluation.
Newman
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Clinical Pharmacology Resource Facility, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Chen
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Madden
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D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D003374:Coumarins / Q000737:chemistry* / Q000493:pharmacokinetics*; D004355:Drug Stability; D006207:Half-Life; D008297:Male; D051379:Mice; D039681:Pyranocoumarins; D013237:Stereoisomerism
D019380:Anti-HIV Agents; D003374:Coumarins; D039681:Pyranocoumarins; C114573:dihydrocalanolide A; C075959:calanolide A