99614-14-9Relevant articles and documents
Metabolite kinetics of ondansetron in rat. Comparison of hepatic microsomes, isolated hepatocytes and liver slices, with in vivo disposition
Worboys,Brennan,Bradbury,Houston
, p. 897 - 907 (2007/10/03)
The kinetics of hydroxylation and N-demethylation of ondansetron have been determined in freshly isolated hepatocytes, hepatic microsomes and precision-cut liver slices from the male Sprague-Dawley rat. In vivo studies have also been carried out to characterize the pharmacokinetics of ondansetron and in vitro data have been assessed for their value as predictors of hepatic clearance. In the three in vitro systems, the formation of hydroxylated and demethylated metabolites were characterized as a function of substrate concentration by a high-affinity, low-capacity site and a low-affinity, high-capacity site which was not saturated over the concentration range studied (2.5-500 μM). Slices gave consistently higher K(m)'s (20 and 30 μM for hydroxylation and demethylation respectively) than hepatocytes (3 and 13 μM respectively) and microsomes (2 and 5 μM respectively). The rank order of V(max) and CL(int) was the same for each system; hydroxylation rates exceeding demethylation rates. Although two hydroxylations (7- and 8-hydroxy metabolites) occurred exclusively in microsomes, these are believed to originate from a common precursor. The high CL(int) of ondansetron (150 ml/min/SRW, where SRW is a standard rat weight of 250 g) is well predicted by scaling either microsomal clearance for microsomal protein recovery or hepatocyte clearance for hepatocellularity (212 and 135 ml/min/SRW respectively). In contrast, the use of liver slice data scaled to a whole liver substantially underestimates CL(int) (9 ml/min/SRW).
Process for preparing N-heterocyclic compounds
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, (2008/06/13)
The invention relates to a process for the preparation of compounds of general formula (I) STR1 wherein R 1 represents a hydrogen atom or a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-(C 1-4)alkyl, C 3-6 alkenyl, C 3-10 alkynyl, phenyl or phenyl-(C 1-3)alkyl group, and one of the groups represented by R 2, R 3 and R 4 is a hydrogen atom or a C 1-6 alkyl, C 3-7 cycloalkyl, C 2-6 alkenyl or phenyl-phenyl-(C 1-3)alkyl group and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C 1-6 alkyl group; or a salt or protected derivative thereof by cyclization of a compound of general formula (II) STR2 wherein X represents a hydrogen atom or a halogen atom and R 1, R 2, R 3 and R 4 are as defined above, or a salt or a protected derivative thereof.The compounds of formula (I) are potent and selective antagonists at ""neuronal"" 5-hydroxytryptamine receptors.
