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Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition

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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.

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Abbreviations

AIC:

Akaike’s Information Criterion

AUC:

Area under the plasma concentration-time curve

Cmax :

Maximum plasma concentration

EHC:

Enterohepatic cycling

F:

Oral bioavailability

Ki :

Inhibitory constant

LC/MS/MS:

Liquid chromatography coupled to tandem mass spectroscopy

MCT1:

Monocarboxylate transporter 1

M-M:

Michaelis-Menten

NCA:

Non-compartmental analysis

PK:

Pharmacokinetics

SC:

Schwarz Criterion

TMDD:

Target-mediated drug disposition

Vss :

Volume of distribution at steady state

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Acknowledgments

The authors would like to thank Dr. Donald E. Mager for his insightful comments and helpful suggestions on the manuscript. This work was funded by the National Institute of Health National Institute on Drug Abuse [grant DA023223]. X.G. was funded in part by an Allen Barnett Fellowship.

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Authors and Affiliations

Authors

Contributions

Participated in research design: Guan and Morris.

Conducted experiments: Guan.

Contributed new reagents or analytic tools: Guan and Morris.

Performed data analysis: Guan and Morris.

Wrote or contributed to the writing of the manuscript: Guan and Morris

Corresponding author

Correspondence to Marilyn E. Morris.

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Conflict of Interest

The authors declare no conflict of interests. This research was performed during the time X.G. was in the Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo. X.G. is currently an employee of AbbVie Inc.

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Guan, X., Morris, M.E. Pharmacokinetics of the Monocarboxylate Transporter 1 Inhibitor AZD3965 in Mice: Potential Enterohepatic Circulation and Target-Mediated Disposition. Pharm Res 37, 5 (2020). https://doi.org/10.1007/s11095-019-2735-z

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