Short Communication POSSIBLE INVOLVEMENT OF ORGANIC ANION TRANSPORTER 2 ON THE INTERACTION OF THEOPHYLLINE WITH ERYTHROMYCIN IN THE HUMAN LIVER

Organic anion transporter 2 (Oat2 [SLC22A7]) is a multispecific organic anion transporter. Although several substrates of human Oat2 (hOat2) have been elucidated, a possible involvement of hOat2 in drug interaction is less defined. The purpose of this study was to investigate the interaction of theophylline with erythromycin mediated by hOat2 using a Xenopus laevis oocyte expression system. When expressed in Xenopus oocytes, hOat2 mediated the transport of theophylline and erythromycin. The finding indicates that the two compounds are novel substrates for hOat2. The apparent Km values for the uptake of hOat2 that mediated the transport of theophylline and erythromycin were 12.6 M and 18.5 M, respectively. The hOat2-mediated uptake of [C]theophylline and [C]erythromycin was cis-inhibited by adding erythromycin and theophylline, respectively. Our present findings suggest that hOat2 may, at least in part, be involved in the theophylline-erythromycin interaction in the human liver. The liver is a central organ for the detoxification and elimination of a wide variety of organic compounds. Several distinct liver-predominant multispecific organic anion transporters such as multidrug resistance associated proteins (MRP1–5[ABCC1–5]) and organic aniontransporting polypeptides (OATP1A2[SLCO1A2], 1B1[SLCO1B1], 1B3[SLCO1B3], 2B1[SLCO2B1]), and Oat5[SLC22A10]) have been isolated and well characterized (Cole and Deeley, 1993; Simonson et al., 1994; Allikmets et al., 1996; Ito et al., 1998; Sun et al., 2001; Hagenbuch and Meier, 2004). To date, five different human Oat isoforms (hOat1–5) have been isolated (Sun et al., 2001). Although the role of hOat5 has not been characterized yet, hOat2 is considered to be one of the key molecules in hepatic handling of organic anions because this isoform is highly expressed in the human liver (Sun et al., 2001). Theophylline, 1,3-dimethylxanthine, has been widely used as a bronchodilatory drug for the treatment of neonatal apnea in premature newborns and patients with chronic obstructive airway disease such as asthma and bronchitis. Theophylline is metabolized by N-demethylation to 1-methylxanthine and 3-methylxanthine and by 8-hydroxylation to 1,3-dimethyluric acid in the liver (Fuhr et al., 1992). It is well known that many drugs increase or decrease the clearance of theophylline, probably by interaction with one or more of the cytochrome P450 species (P450s). It has been reported that theophylline is metabolized by CYP1A2, 1B1, 2E1, and 3A4 (Sarkar et al., 1992; Ha et al., 1995; Rasmussen et al., 1995; Shimada et al., 1997). Since the frequency and severity of toxicity from theophylline increases as serum concentrations exceed 20 g/ml and efficacy is diminished as levels decline below 10 g/ml, the administration of a second drug that alters the elimination of theophylline has potential clinical relevance (Jenne et al., 1972; Mangione et al., 1978; Aslaksen et al., 1981). Macrolide antibiotics such as erythromycin have been used for treatment of a variety of infections and are often combined with other drug therapies. For example, patients with chronic asthma receiving continuous therapy with theophylline may require short courses of erythromycin for unrelated pyogenic infections. It has been reported that serum theophylline concentrations increased in patients with concomitant administration of erythromycin by inhibiting hepatic P450s (Cummins et al., 1976; Kozak et al., 1977; Pfeifer et al., 1979). However, it is not clear at this time whether such a drug interaction could be mediated by drug transporters. In the present study, therefore, we investigated the possible involvement of hOat2 in the interaction of theophylline with erythromycin. Materials and Methods Chemicals. [C]Theophylline (52 mCi/mmol) and [C]erythromycin (55 mCi/mmol) were purchased from American Radiolabeled Chemicals (St. Louis, MO). All other chemicals were of the highest grade commercially