title: 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 > or =75 mg/kg/day, while in rats and monkeys it did not appear at doses up to 1500 and 2000 mg/kg/day 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, > or =90%, 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 micromol/l was obtained at plasma concentrations approximately similar to those at which hepatobiliary toxicity occurred, while in rat and monkey the levels were < or =7000 micromol/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 (Påhlman et al. 1999), it is likely that the hepatotoxic findings in dog are induced by the high concentrations of susalimod in the bile duct.
authors.affiliation: Department of Drug Metabolism Research, Pharmacia & Upjohn, Sweden. ingrid.pahlman@hassle.se.astra.com
authors.forename: I
authors.initials: I
authors.lastname: Påhlman
authors.forename: S
authors.initials: S
authors.lastname: Andersson
authors.forename: K
authors.initials: K
authors.lastname: Gunnarsson
authors.forename: M L
authors.initials: ML
authors.lastname: Odell
authors.forename: M
authors.initials: M
authors.lastname: Wilén
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001565:Benzoates / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D001646:Bile / Q000378:metabolism*; D001652:Bile Ducts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001663:Bilirubin / Q000097:blood; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D012460:Sulfasalazine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D001565:Benzoates; D012460:Sulfasalazine; C119880:susalimod; D001663:Bilirubin