Abstract
Caspofungin (CANCIDAS, a registered trademark of Merck & Co., Inc.) is a novel echinocandin antifungal agent used in the treatment of esophageal and invasive candidiases, invasive aspergillosis, and neutropenia. Available data suggest that the liver is a key organ responsible for caspofungin elimination in rodents and humans. Caspofungin is primarily eliminated by metabolic transformation; however, the rate of metabolism is slow. Accordingly, it was hypothesized that drug uptake transporters expressed on the basolateral domain of hepatocytes could significantly influence the extent of caspofungin uptake and subsequent elimination. In this study, experiments ranging from perfused rat livers to heterologous expression of individual hepatic uptake transporters were utilized to identify the transporter(s) responsible for the observed liver-specific uptake of this compound. Data from perfused rat liver studies were consistent with the presence of carrier-mediated caspofungin hepatic uptake, although this process appeared to be slow. To identify a relevant hepatic uptake transporter, we developed novel Tet-on HeLa cells expressing OATP1B1 (OATP-C, SLC21A6) and OATP1B3 (OATP8, SLC21A8), whose target gene can be overexpressed by the addition of doxycycline. A modest but statistically significant uptake of caspofungin was observed in cells overexpressing OATP1B1, but not OATP1B3. Taken together, these findings suggest that OATP1B1-mediated hepatic uptake may contribute to the overall elimination of this drug from the body.
Footnotes
-
This work was supported in part by United States Public Health Service Grants GM54724, GM31304, and a Grant-in-Aid from Merck Research Laboratories.
-
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
-
doi:10.1124/dmd.104.003244.
-
ABBREVIATIONS: NTCP, sodium-dependent taurocholate-cotransporting polypeptide; OAT, organic anion transporter; OATP, organic anion-transporting polypeptide; OCT, organic cation transporter; Hyg, hygromycin; P-gp, P-glycoprotein; VBL, vinblastine; SNP, single nucleotide polymorphism.
-
↵1 Current address: Department of Drug Safety and Metabolism, Wyeth Pharmaceuticals, 1 Burtt Rd., Andover, MA.
-
↵2 Current address: Department of Pharmacokinetics and Drug Metabolism, Amgen, Thousand Oaks, CA.
- Received December 10, 2004.
- Accepted February 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|