[Physiological principles of imipramine pharmacokinetics]

Part I. Assessment of hepatic elimination of IMI based on the in vivo, in vitro an isolated rat liver perfusion experimental data. The isolated rat liver perfusion was carried out acc. to Miller at two different hepatic blood flow 6 and 11 ml/min respectively. The postmitochondrial liver fraction (9000 g) as a source of enzymes metabolized of IMI was incubated acc. to Nakazawa to estimate Vm, Km and Clintr values. Based on these enzymatic parameters and using ("well stirred") model of hepatic elimination, the hepatic clearance (ClH) and hepatic extraction ratio (E) of IMI were predicted and compared with the values derived from perfusion experiments as well as from in vivo studies. A good agreement was obtained between predicted and observed ClH and E values. It was found that systemic clearance of IMI is similar to hepatic clearance and is affected by change in hepatic blood flow. The hepatic elimination of IMI is unaffected by protein binding of this drug and both free and bound fraction were available for metabolism. Part II. Studies on the rat brain transport of IMI. Using Oldendorf's method (BUI method) the rat brain uptake of 3H-IMI in the presence of unlabeled IMI (0.25-250 microM) as well as after multiple dosing of IMI was studied. It was found, that the transport of 3H-IMI through blood brain barrier was nonsaturable up to 250 microM, what can reflect the transport via passive diffusion. Only very high brain concentration of IMI can inhibited the brain uptake of 3H-IMI. The uptake of 3H-IMI is not restrictive by plasma protein binding of this compound.