Intrahepatic distribution of hydrochlorothiazide and quinidine in rats: implications in pharmacokinetics

The intrahepatic distributions of a nonmetabolized drug, hydrochlorothiazide (HCTZ) and a highly metabolized drug, quinidine (QD), were studied separately in five anesthetized rats during steady-state intravenous infusion. Liver samples (20-24) from various parts (0.1-0.2 g each) at the end of infusion were collected from each rat and analyzed for drug concentration by HPLC. The distribution of HCTZ in various macro regions appears quite "homogeneous," with a CV of drug concentration for each rat ranging from 2.6 to 4.7% (grand mean, 3.7 +/- 0.8%), whereas that of QD seems less "homogeneous," with a CV ranging from 8.5 to 28.3% (grand mean, 15.6 +/- 7.7%). The above results indicate that drugs that are not complicated by hepatic metabolism may tend to show more "homogeneous" distribution and those that are highly metabolized and/or known to strongly bind to hepatic tissue component(s) may show less "homogeneous" distribution. The results from the present QD study are in contrast with the general, much more heterogeneous distribution found in an isolated in situ perfusion study reported earlier. The implication of the present study in physiological pharmacokinetic and hepatic modeling is discussed.