Summary
Pharmacokinetic processes have been studied using a recirculating rat liver perfusion system. Imipramine and its major metabolites have been determined at various times up to 3 h in perfusate, liver, bile and subcellular liver fractions.
Imipramine undergoes a rapid hepatic uptake, the initial extraction being close to 100%. Most of the unchanged drug is then localized in the microsomal fraction. Metabolism is not limited by uptake and follows the pathways known from previous work. Like imipramine, its lipophilic metabolite, desmethylimipramine is bound to microsomes. Its concentration ratios, endoplasmic reticulum/cytosol and liver/perfusate, are around 200. In contrast, the polar glucuronides are easily released from the ER, their site of formation, into the cytosol and presumably from there excreted into the bile. A smaller amount of the glucuronides is increted into the perfusate where they reach a steady state level. Analogous experiments with a non-recirculating perfusion system yielded comparable results except for a more rapid imipramine uptake.
The results obtained in this study suggest that the pharmacokinetics of many drugs with high apparent volumes of distribution may be largely governed by intracellular binding of lipophilic compounds and translocation processes of polar metabolites.
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Bickel, M.H., Börner, H. Uptake, subcellular distribution, and transfer processes of imipramine and its metabolites formed in rat liver perfusion systems. Naunyn-Schmiedeberg's Arch. Pharmacol. 284, 339–352 (1974). https://doi.org/10.1007/BF00504703
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DOI: https://doi.org/10.1007/BF00504703