Hepatic Uptake of the Novel Antifungal Agent Caspofungin

Abstract

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.

In Vitro Investigation of the Hepatobiliary Disposition Mechanisms of the Antifungal Agent Micafungin in Humans and Rats

“…Nevertheless, very little is known regarding the possible role of transporters in hepatobiliary elimination of micafungin in rats (Abe et al, 2008b), and no information is available in humans. In contrast, for another echinocandin, caspofungin, the active transport mechanisms possibly mediating its hepatic uptake have been investigated in experiments that used HeLa cells heterologously expressing the hepatic OATP isoforms (Sandhu et al, 2005). These uptake transporters have been suggested to play key roles in the hepatic elimination of caspofungin.…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…No inhibition of P-gp 96 Substrate and inhibitor of OAT1B1. 96 CYP3A4 inhibition by caspofungin causes a 76% decrease in the metabolism of cytarabine.…”

“…96 CYP3A4 inhibition by caspofungin causes a 76% decrease in the metabolism of cytarabine. 187 CYP inducers (e.g., rifampin, nevirapine, efavirenz, carbamazepine, dexamethasome and phenytoin) induce the metabolism of caspofungin.…”

“…Its plasma profile is determined primarily by its rate of distribution from plasma into tissues, rather than by metabolism or excretion. 95 Uptake occurs into hepatocytes via an initial rapid reversible adsorption to the cell surface and a second slow phase of transport across the cell membrane, 95,96 mediated by organic anion transporter protein 1B1 (OATP1B1). 96 Interactions with other transporters are detailed in Table 4.…”

Elucidating the Effect of Final-Day Dosing of Rifampin in Induction Studies on Hepatic Drug Disposition and Metabolism

“…Results from a clinical study conducted by Stone et al (2004) suggested that RIF both induced and inhibited the disposition of caspofungin, which has been shown to be a substrate of OATP1B1 (Sandhu et al, 2005). In another clinical study, when RIF and repaglinide were coadministered, RIF acted as an inducer and inhibitor of repaglinide metabolism (Bidstrup et al, 2004).…”