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Antimicrobial Agents and Chemotherapy, September 2007, p. 3230-3234, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00082-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Roles of P-Glycoprotein, Bcrp, and Mrp2 in Biliary Excretion of Spiramycin in Mice{triangledown}

Xianbin Tian,1,{dagger} Jun Li,1 Maciej J. Zamek-Gliszczynski,1,{ddagger} Arlene S. Bridges,1 Peijin Zhang,1,§ Nita J. Patel,2 Thomas J. Raub,2 Gary M. Pollack,1 and Kim L. R. Brouwer1*

School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina,1 Eli Lilly and Company, Drug Disposition, Indianapolis, Indiana2

Received 19 January 2007/ Returned for modification 7 March 2007/ Accepted 7 June 2007

The multidrug resistance proteins P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and multidrug resistance-associated protein 2 (Mrp2) are the three major canalicular transport proteins responsible for the biliary excretion of most drugs and metabolites. Previous in vitro studies demonstrated that P-gp transported macrolide antibiotics, including spiramycin, which is eliminated primarily by biliary excretion. Bcrp was proposed to be the primary pathway for spiramycin secretion into breast milk. In the present study, the contributions of P-gp, Bcrp, and Mrp2 to the biliary excretion of spiramycin were examined in single-pass perfused livers of male C57BL/6 wild-type, Bcrp-knockout, and Mrp2-knockout mice in the presence or absence of GF120918 (GW918), a P-gp and Bcrp inhibitor. Spiramycin was infused to achieve steady-state conditions, followed by a washout period, and parameters governing spiramycin hepatobiliary disposition were recovered by using pharmacokinetic modeling. In the absence of GW918, the rate constant governing spiramycin biliary excretion was decreased in Mrp2– knockout mice (0.0013 ± 0.0009 min–1) relative to wild-type mice (0.0124 ± 0.0096 min–1). These data are consistent with the ~8-fold decrease in the recovery of spiramycin in the bile of Mrp2-knockout mice and suggest that Mrp2 is the major canalicular transport protein responsible for spiramycin biliary excretion. Interestingly, biliary recovery of spiramycin in Bcrp-knockout mice was increased in both the absence and presence of GW918 compared to wild-type mice. GW918 significantly decreased the rate constant for spiramycin biliary excretion and the rate constant for basolateral efflux of spiramycin. In conclusion, the biliary excretion of spiramycin in mice is mediated primarily by Mrp2 with a modest P-gp component.

* Corresponding author. Mailing address: Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, C.B. 7360, Kerr Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. Phone: (919) 962-7030. Fax: (919) 962-0644. E-mail: kbrouwer{at}unc.edu

{triangledown} Published ahead of print on 18 June 2007.

{dagger} Present address: Wyeth, Discovery Pharmacokinetics, Andover, MA.

{ddagger} Present address: Eli Lilly and Company, Drug Disposition, Indianapolis, IN.

§ Present address: MPI Research, Mattawan, MI.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3230-3234, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00082-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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