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I'm working with a compound that has a carboxylic acid moiety. This
compound is intended for once a day oral administration. I've been
asked to predict the half-life in humans. Briefly, I summarise what I
know of the compound. In vivo, the half-life in rat is very similar
to that obtained in dog. The in vitro data I've got in hepatic
microsomes show a metabolic rate that varies across species: dog <<
rat and human << monkey. The study of glucuronidation in rat and
human microsomes show similar percentages of glucuronide formed in
both species. I still have no information about glucuronidation in
microsomes from other species, metabolic clearance in hepatocytes or
about which are the main routes of elimination, at least in rat.
My questions are related to how to predict the half-life in humans.
Which species should I chose to do the allometric scaling considering
the in vitro metabolism data I have? should be correct to predict
human clearance using in vitro data from human hepatocytes providing
that a correlation in vitro-in vivo for rat is found? Have someone
come across with the same problem or know from the literature some
examples? Any hint how to approach this issue will be welcomed.
Thanks for your help
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Preclinical data from monkeys is thought to deliver the most accurate
predictions of human PK (Ward & Smith, Drug metabolism and
disposition 32:603-611, 2004)
On the other hand, preclinical data obtained from smaller vertebrates
such as dogs and especially rats is very often employed in prediction
of human PK parameters. It all depends on how close you want to get.
In another article (Ward&Erhard, Journal of Pharmacological and
Toxicological Methods 51:57-64, 2005) I have read that less than 60%
of the tested drug's half lives were acceptably predictied from rat
half lives.(2 fold acceptance margin).
In our lab, not only quantitative but also qualitative differences in
glucuronidation between rat and human microsomes were observed.
Although your suggestion to extrapolate human hepatocyte data based
on good in vivo / in vitro correlation in rats does seem sound, I
would still advise caution and maybe use another non-rodent animal,
for instance, a pig.
Have you also considered a pre-systemic metabolism of your NCE that
can occur in the gut wall ? This is an important site of
glucuronidation if the drug is intended for peroral use.
Faculty of pharmacy
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