Extensive Biliary Excretion of the Sulfasalazine Analogue, Susalimod, but Different Concentrations in the Bile Duct in Various Animal Species Correlating to Species‐Specific Hepatobiliary Toxicity

Abstract

Studies on biliary concentrations of susalimod were conducted in rat, dog and monkey to clarify the interspecies differences observed in toxicology studies with respect to hepatobiliary toxicity after long-term administration of the compound. Dose-related bile duct hyperplasia appeared only in dogs at doses 2 7 5 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mglkglday respectively. Biliary excretion was investigated after intraduodenal administration of susalimod in anaesthetised animals. In addition excretion routes were determined by collecting urine and faeces following a radiolabelled intravenous dose. Susalimod was extensively excreted via the bile in all animal species, ~9 0 % 1 , mainly as non-conjugated parent compound. However, the local concentrations in bile varied between the species. Highest concentrations were obtained in the dog. The bile/plasma concentration ratio was 3400 in the dog, 300 in the monkey and 50 in the rat. In the dog, bile duct concentrations of susalimod about 30,000 pmolll was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were 57000 pmol/l at plasma concentrations similar to those obtained at the highest doses in the toxicology studies. From these results supported by a previous biliary excretion study in conscious dogs with chronic bile fistula receiving repeated administration of susalimod (Pihlman et ul. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.Susalimod ( fig. 1) was developed based on experience with sulfasalazine. Sulfasalazine has been used in the treatment of inflammatory bowel disease for more than 50 years, based on the principle of a local effect of active metabolites formed by bacterial azoreductase in the colon, 5-aminosalicylic acid and sulfapyridine (Peppercorn 1990). In recent years the drug has also been successfully used in rheumatoid arthritis (Rains et al. 1995). It has been postulated that the beneficial effect observed in rheumatoid arthritis might be attributed to the parent drug rather than its metabolites (Pullar rt ul. 1985;Neuman et al. 1986). Susalimod was designed to retain sulfasalazine's immunomodulating activities of importance in the treatment of rheumatoid arthritis, such as inhibition of the production of proinflammatory cytokines and suppression of the proliferation of lymphocytes (Williams et a/. 1993). The chemical modification of sulfasalazine also aimed at stabilizing the molecule in the presence of azoreductase, and to increase lipophilicity for improving the intestinal absorption. Although the absorption of susalimod was increased up to ten times compared to sulfasalazine in a rat intestinal absorption model (Pihlman, unpublished results), preliminary preclinical pharmacokinetic studies exhibited only low systemic exposure in animals, indicating a high first-pass elimination. Species-specific bile duct toxicity ap...

Physiologically Based Pharmacokinetic (PBPK) Modeling of Disposition of Epiroprim in Humans

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Quantitative Expression Profile of Hepatobiliary Transporters in Sandwich Cultured Rat and Human Hepatocytes

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LC−MS/MS Mediated Absolute Quantification and Comparison of Bile Salt Export Pump and Breast Cancer Resistance Protein in Livers and Hepatocytes across Species

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