1. Pharmacokinetic modeling to assess factors affecting the oral bioavailability of the lactone and carboxylate forms of the lipophilic camptothecin analogue AR-67 in rats.
- Author
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Adane ED, Liu Z, Xiang TX, Anderson BD, and Leggas M
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters antagonists & inhibitors, Acridines administration & dosage, Acridines pharmacology, Administration, Oral, Animals, Antineoplastic Agents, Phytogenic administration & dosage, Camptothecin administration & dosage, Carboxylic Acids administration & dosage, Carboxylic Acids blood, Carboxylic Acids chemistry, Female, Lactones administration & dosage, Lactones blood, Lactones chemistry, Models, Biological, Rats, Rats, Sprague-Dawley, Tetrahydroisoquinolines administration & dosage, Tetrahydroisoquinolines pharmacology, Topoisomerase I Inhibitors administration & dosage, Antineoplastic Agents, Phytogenic blood, Antineoplastic Agents, Phytogenic chemistry, Camptothecin analogs & derivatives, Camptothecin blood, Topoisomerase I Inhibitors blood, Topoisomerase I Inhibitors chemistry
- Abstract
Purpose: Camptothecin analogues are anticancer drugs effective when dosed in protracted schedules. Such treatment is best suited for oral formulations. AR-67 is a novel lipophilic analogue with potent efficacy in preclinical models. Here we assessed factors that may influence its oral bioavailability in rats., Methods: Plasma pharmacokinetic (PK) studies were conducted following administration of AR-67 lactone or carboxylate doses alone or after pre-dosing with inhibitors of the efflux transporters P-gp and Bcrp. A population PK model that simultaneously fitted to oral and intravenous data was used to estimate the bioavailability (F) and clearance of AR-67., Results: An inverse Gaussian function was used as the oral input into the model and provided the best fits. Covariate analysis showed that the bioavailability of the lactone, but not its clearance, was dose dependent. Consistent with this observation, the bioavailability of AR-67 increased when animals were pretreated orally with GF120918 or Zosuquidar., Conclusion: Absorption of AR-67 is likely affected by solubility of its lactone form and interaction with efflux pumps in the gut. AR-67 appears to be absorbed as the lactone form, most likely due to gastric pH favoring its formation and predominance. F increased at higher doses suggesting saturation of efflux mechanisms.
- Published
- 2012
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