Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter
Introduction
Methotrexate is administered for the treatment of various malignancies in high doses or for the treatment of rheumatoid arthritis and psoriasis in low doses Frei et al., 1975, Jackson, 1984, Bannwarth et al., 1996. The agent is mainly excreted in urine, almost entirely in a nonmetabolized form, and the renal tubular secretion of methotrexate by organic anion transporters is the main route for its elimination Huffman et al., 1973, Liegler et al., 1969. It has been reported that probenecid, a potent inhibitor of renal organic anion transporters, increases the half-life and area under the curve (AUC) of the serum concentration of methotrexate, which are associated with the adverse effects of methotrexate (McLeod, 1998).
In the management of rheumatoid arthritis, methotrexate is given concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (Bannwarth et al., 1996). However, there are several clinical observations that suggest that coadministration of these drugs induces severe methotrexate toxicity such as bone marrow depression, mucositis, hepatitis or renal insufficiency Maiche, 1986, Thyss et al., 1986. Possible mechanisms for the toxic effects due to their simultaneous administration are that unbound serum levels of methotrexate are increased by displacement from protein binding sites and that the inhibition of prostaglandin synthesis by NSAIDs leads to decreased renal clearance of methotrexate (Bannwarth et al., 1996). Nierenberg (1983) showed that NSAIDs inhibit methotrexate uptake in rabbit kidney slices. Among these mechanisms, the inhibition of renal tubular secretion of methotrexate by NSAIDs has been suggested to be the most potent Nierenberg, 1983, Statkevich et al., 1993.
Methotrexate causes the acute nephrotoxicity as a result of its intratubular precipitation (El-Badawi et al., 1996). In addition, the Rheumatoid Arthritis Clinical Trial Archive Group (1995) reported that the decline of renal function due to age or renal insufficiency is a potent risk for development of methotrexate nephrotoxicity. Despite methotrexate-induced nephrotoxicity being related to its renal handling, the precise mechanism for tubular secretion and/or reabsorption of methotrexate remains to be solved. Therefore, it is important to elucidate the detailed renal handling of methotrexate in order to avoid drug–drug interactions or renal failure caused by methotrexate.
To date, the transporters that principally mediate renal tubular secretion of methotrexate have not been identified. However, according to the studies by Nierenberg (1986) and Besseghir et al. (1989), methotrexate could be taken up by renal tubular cells via the transport system mediating p-aminohippurate uptake. In fact, the cloned rat kidney organic anion transporter OAT1 has been suggested to recognize methotrexate as a substrate Sekine et al., 1997, Uwai et al., 1998.
In the present study, we investigated the inhibitory effects of NSAIDs and probenecid on rOAT1-mediated methotrexate transport, using the Xenopus laevis oocyte expression system, to obtain information on the molecular aspects of the mechanisms of the NSAID-induced increase in serum methotrexate levels. The findings of the present study suggest that rOAT1 is the site where methotrexate interacts with NSAIDs or probenecid, leading to its side effects.
Section snippets
Materials
p-[Glycyl-14C]aminohippurate (1.9 GBq/mmol) and [3′,5′,7-3H(N)]methotrexate (991.6 GBq/mmol) were purchased from Du Pont-New England Nuclear Research Product (Boston, MA, USA) and Moravek Biochemicals, (Brea, CA), respectively. Phenylbutazone, salicylate and unlabeled methotrexate (l-(+)-amethopterin) were obtained from Nacalai Tesque (Kyoto, Japan). Flufenamate, ibuprofen, indomethacin and ketoprofen were from Wako (Osaka, Japan). Other chemicals of the highest purity were purchased from Sigma
Interaction of methotrexate and probenecid with rOAT1
Fig. 1 shows rOAT1-mediated uptake of a typical rOAT1 substrate, p-[14C]aminohippurate, and [3H]methotrexate uptake. Uptake of the two compounds was markedly stimulated in rOAT1 cRNA-injected oocytes. The rOAT1-mediated uptake clearance of p-aminohippurate was about 15-fold higher than that of methotrexate. The uptake of both compounds was markedly inhibited by the potent organic anion transport system inhibitor, probenecid.
Next, to determine the affinity of probenecid and methotrexate for
Discussion
The main elimination route of methotrexate is considered to be renal tubular secretion by organic anion transporters in the proximal tubules (Liegler et al., 1969). Previous studies suggested that rOAT1 is the major transporter for p-aminohippurate uptake from blood to renal epithelial cells at the basolateral membranes of proximal tubular cells Sekine et al., 1997, Sweet et al., 1997, Uwai et al., 1998. Nierenberg (1986) suggested that the p-aminohippurate transport pathway in proximal tubule
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan, a grant from the Yamanouchi Foundation for Research on Metabolic Disorders, and a grant from the Uehara Memorial Foundation.
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