Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A)

Abstract

Histamine H₂ receptor antagonist famotidine and cimetidine are commonly used for treatment of gastrointestinal ulcer diseases. Inasmuch as these drugs are mainly secreted by renal tubules, dosages have been adjusted according to renal function. Although many studies have been performed on the molecular mechanisms of renal handling of cimetidine, little is known about that of famotidine. In this study, to examine the recognition and transport of famotidine by human organic anion transporters (OATs; hOAT1, hOAT3) and human organic cation transporter (OCT; hOCT2), the uptake studies using Xenopus laevis oocytes were performed in comparison with cimetidine. The half-maximal inhibitory concentrations of famotidine for [³H]estrone sulfate transport by hOAT3 and [¹⁴C]tetraethylammonium transport by hOCT2 (300 μM and 1.8 mM, respectively) were higher than those of cimetidine (53 and 67 μM, respectively). While cimetidine inhibited p-[¹⁴C]aminohippurate transport by hOAT1 in a concentration dependent manner, famotidine did not affect it at 5 mM. In addition, hOAT3 mediated famotidine uptake, but hOAT1 and hOCT2 did not show famotidine transport. These results indicate that there are marked differences between famotidine and cimetidine in the recognition and transport by organic ion transporters and that hOAT3 contributes to the renal tubular secretion of famotidine. Present findings should be useful information to understand the renal handling of famotidine and cimetidine.

Introduction

A histamine H₂ receptor antagonist famotidine is commonly used in the treatment for gastrointestinal ulcer diseases. Famotidine shows beneficial characteristics, including stronger inhibition of gastric acid secretion, longer acting and less interaction with P-450, compared with another histamine H₂ receptor antagonist cimetidine (Howard et al., 1985, Humphries, 1987). Pharmacokinetic studies revealed that famotidine was mainly excreted into the urine as an unmetabolized form (Takabatake et al., 1985, Lin et al., 1988, Dowling et al., 2001). Renal clearance of famotidine exceeded the creatinine clearance about three times in subjects with normal renal function, indicating the efficient tubular secretion of the drug. In patients with renal insufficiency, plasma elimination and renal clearance of famotidine were significantly decreased (Takabatake et al., 1985, Lin et al., 1988). To avoid the accumulation and undesirable effects, famotidine dosage should be reduced according to the renal functions.

In this decade, organic anion transporters (OATs) and organic cation transporters (OCTs) in the kidney were identified, and their characteristics have been clarified. These transporters mediate endogenous and exogenous substances, such as uremic toxins, diuretics, methotrexate, antibiotics, antivirals and nonsteroidal antiinflammatory drugs, suggesting that OATs and OCTs are responsible for the tubular secretion of these compounds (Inui et al., 2000, Sekine et al., 2000, Dresser et al., 2001). Recently, we quantified mRNA levels of organic ion transporters in the human kidney cortex and revealed that hOAT1 (SLC22A6), hOAT3 (SLC22A8) and hOCT2 (SLC22A2) mRNA were higher than other organic ion transporters (Motohashi et al., 2002). Moreover, hOAT1, hOAT3 and hOCT2 protein localized at the basolateral membrane of the renal proximal tubules. Accordingly, these transporters play important roles for the renal uptake of organic compounds from the circulation.

It has been assumed that the renal tubular secretion of famotidine and cimetidine would be mediated by OCTs due to their cationic property at the physiological pH (Fig. 1). Indeed, cimetidine inhibits the renal secretion of various organic cations (Somogyi et al., 1983, Christian et al., 1984, van Crugten et al., 1986) and Urakami et al., 2001, Urakami et al., 2002 indicated that rat and human organic cation transporters rOCT1, rOCT2 and hOCT2 transported cimetidine. However, in addition to hOCT2, hOAT1, hOAT3 and rOAT3 were shown to transport the cimetidine. (Kusuhara et al., 1999, Cha et al., 2001, Burckhardt et al., 2003). Therefore, it was supposed that these three transporters were concerned with renal secretion of cimetidine. While famotidine is more frequently used than cimetidine because of it beneficial characteristics, adverse effects associated with famotidine, such as thrombocytopenia (Wade et al., 2002) or central nerve system reaction (Yoshimoto et al., 1994), have been reported. Although dosage should be adjusted according to renal function, molecular mechanisms of renal secretion of famotidine have not been investigated in contrast to cimetidine. To understand the renal handling of famotidine, it should be examined whether hOATs or hOCTs recognize and transport famotidine.

The purpose of the present study is to clarify the recognition and transport properties of famotidine by hOAT1, hOAT3 and hOCT2 in comparison with cimetidine. We performed transport experiments of famotidine and cimetidine using Xenopus laevis oocytes expressing these organic ion transporters.