Biotransformation of a somatostatin analogue in precision-cut liver and kidney slices from rat, dog and man

Abstract

1. Cleavage of the glucopyranosyl moiety of the somatostatin analogue SDZ CO 611 results in the formation of the major metabolite, SDZ CO 610, in liver and kidney slices of rat, dog and man, as well as in liver S9 and cytosol of rat and man. 2. The rates of SDZ CO 610 formation (nmol/h/mg slice protein) for all three species were determined in liver slices for 24 h and the relative order was: rat (0.12) > dog (0.096) = man (0.095). The rates of SDZ CO 610 formation (nmol/h/mg slice protein) for all three species in kidney were determined, and the relative order was: rat (0.29) > dog (0.16) > man (0.10). 3. SDZ CO 610 was rapidly formed by rat gut contents in the absence of NADPH, possibly by disaccharide-splitting enzymes. 4. Biotransformation of SDZ CO 611 to SDZ CO 610 in human and rat liver S9 and cytosol was similar to that found in liver slices cultures indicating that cleavage of the glucopyranosyl moiety of SDZ CO 611 could occur in the presence and in the absence of cytochrome P450, possibly by glucosidases in liver cytosol. 5. Rat intestinal homogenate also formed SDZ CO 610 but metabolism was dependent upon NADPH, suggestive of a cytochrome P450-dependent reaction.

Workshop Overview: Scientific and Regulatory Challenges for the Reduction, Refinement, and Replacement of Animals in Toxicity Testing,

“…One approach is to compare the effect of a drug in cultured human and animal tissue, providing information about the potential species-specificity of drug-induced adverse effects, otherwise unavailable in the preclinical phase of safety testing. Precisioncut tissue slicing has been a very useful tool in this respect (Smith et al, 1985), and has been increasingly used for interspecies comparisons of toxicity (Fisher et al, 1991(Fisher et al, , 1995Price et al, 1996), metabolism (Steensmae/ al., 1994Connors et al, 1996), liver enzyme induction (Glockner et al, 1995;Heinonen et al, 1996;Lake et al, 1996a), and genotoxicity (Baumann et al, 1996;Beamand et al, 1996;Lake et al, 1996b). Using the same preparative technique in all species, slices are relatively simple to prepare from almost any organ, including important targets of toxicity, such as the liver (Smith et al, 1985), lung (Fisher et al, 1994;Price et al, 1995a,b), and kidney (Ruegg, 1994).…”