Xiaowen Guan1,2, Marilyn E Morris3,4. 1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14214-8033, USA. 2. Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Redwood City, CA, 94063, USA. 3. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, 14214-8033, USA. memorris@buffalo.edu. 4. Department of Pharmaceutical Sciences, University at Buffalo, 445 Pharmacy Building, Buffalo, NY, 14214-8033, USA. memorris@buffalo.edu.
Abstract
PURPOSE: To evaluate the pharmacokinetics (PK) of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drug disposition (TMDD) of AZD3965. METHODS: Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100 mg/kg) or oral gavage (100 mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses. RESULTS: AZD3965 exhibited a large volume of distribution and rapid oral absorption, with a high oral bioavailability. Prominent reentry peaks were observed after both oral and IV administration, suggesting potential EHC of AZD3965 or of a potential glucuronide conjugate. The dose-dependent studies indicated greater than proportional increases in exposure, an increase in the terminal half-life, and decrease in clearance and volume of distribution with increasing IV doses, indicating nonlinear pharmacokinetics and potential TMDD of AZD3965. Mechanistic compartmental models were developed to characterize the complex pharmacokinetics of AZD3965. CONCLUSIONS: The current study represents the first comprehensive report of the pharmacokinetics of AZD3965 in mice, indicating the potential contribution of EHC and TMDD in the disposition of AZD3965.
PURPOSE: To evaluate the pharmacokinetics (PK) of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in mice after IV and oral administration and to develop mechanistic PK models to assess the potential enterohepatic circulation (EHC) and target-mediated drug disposition (TMDD) of AZD3965. METHODS: Female BALB/c mice were administered AZD3965 by IV injection (10, 50 and 100 mg/kg) or oral gavage (100 mg/kg). Plasma samples were analyzed using LC/MS/MS, and PK parameters determined by compartmental and non-compartmental analyses. RESULTS:AZD3965 exhibited a large volume of distribution and rapid oral absorption, with a high oral bioavailability. Prominent reentry peaks were observed after both oral and IV administration, suggesting potential EHC of AZD3965 or of a potential glucuronide conjugate. The dose-dependent studies indicated greater than proportional increases in exposure, an increase in the terminal half-life, and decrease in clearance and volume of distribution with increasing IV doses, indicating nonlinear pharmacokinetics and potential TMDD of AZD3965. Mechanistic compartmental models were developed to characterize the complex pharmacokinetics of AZD3965. CONCLUSIONS: The current study represents the first comprehensive report of the pharmacokinetics of AZD3965 in mice, indicating the potential contribution of EHC and TMDD in the disposition of AZD3965.
Entities:
Keywords:
AZD3965; enterohepatic cycling; monocarboxylate transporters; pharmacokinetics; target-mediated drug disposition
Authors: Candice Sun Hong; Nicholas A Graham; Wen Gu; Carolina Espindola Camacho; Vei Mah; Erin L Maresh; Mohammed Alavi; Lora Bagryanova; Pascal A L Krotee; Brian K Gardner; Iman Saramipoor Behbahan; Steve Horvath; David Chia; Ingo K Mellinghoff; Sara A Hurvitz; Steven M Dubinett; Susan E Critchlow; Siavash K Kurdistani; Lee Goodglick; Daniel Braas; Thomas G Graeber; Heather R Christofk Journal: Cell Rep Date: 2016-02-11 Impact factor: 9.423
Authors: Hui Wang; Chunying Yang; Joanne R Doherty; William R Roush; John L Cleveland; Thomas D Bannister Journal: J Med Chem Date: 2014-08-22 Impact factor: 7.446
Authors: Richard A Noble; Natalie Bell; Helen Blair; Arti Sikka; Huw Thomas; Nicole Phillips; Sirintra Nakjang; Satomi Miwa; Rachel Crossland; Vikki Rand; Despina Televantou; Anna Long; Hector C Keun; Chris M Bacon; Simon Bomken; Susan E Critchlow; Stephen R Wedge Journal: Haematologica Date: 2017-04-06 Impact factor: 9.941
Authors: Caroline Dive; Christopher J Morrow; Radosław Polański; Cassandra L Hodgkinson; Alberto Fusi; Daisuke Nonaka; Lynsey Priest; Paul Kelly; Francesca Trapani; Paul W Bishop; Anne White; Susan E Critchlow; Paul D Smith; Fiona Blackhall Journal: Clin Cancer Res Date: 2013-11-25 Impact factor: 12.531
Authors: Becky M Bola; Amy L Chadwick; Filippos Michopoulos; Kathryn G Blount; Brian A Telfer; Kaye J Williams; Paul D Smith; Susan E Critchlow; Ian J Stratford Journal: Mol Cancer Ther Date: 2014-10-03 Impact factor: 6.261
Authors: Marta Braga; Maciej Kaliszczak; Laurence Carroll; Zachary T Schug; Kathrin Heinzmann; Nicoleta Baxan; Adrian Benito; Gabriel N Valbuena; Stephen Stribbling; Alice Beckley; Gillian Mackay; Francesco Mauri; John Latigo; Chris Barnes; Hector Keun; Eyal Gottlieb; Eric O Aboagye Journal: Cancers (Basel) Date: 2020-06-26 Impact factor: 6.639