Comparison of different clearance estimates for metoprolol in the rhesus monkey

After oral administration, the fraction of unchanged drug available systemically is predominantly governed by hepatic drug-metabolizing enzyme activity and/or binding to the liver. If the "well stirred" model for hepatic elimination mimics reality, the apparent oral clearance (Clo) of metoprolol, a drug which is completely absorbed and metabolized only by the liver, should reflect the intrinsic clearance (Cli), i.e., the maximum enzyme activity in absence of blood flow limitations. According to theory, the hepatic venous (hv) drug concentrations after an i.v. dose are also a function of Cli. This postulate has previously been verified in the isolated perfused rat liver by others and has now been tested by us in the intact rhesus monkey. We have compared Clo, Cli and the systemic clearance (Cls) of metoprolol in six rhesus monkeys catheterized in the hepatic and femoral veins (hv; fv). They were given simultaneously 37 to 73 micrograms of [3H]metoprolol i.v. and 9 mg of metoprolol per kg b.w. orally. Unlabeled drug was analyzed in plasma by gas chromatography and 3H-labeled metoprolol by liquid scintillation after liquid chromatography separation. The Cls [dose i.v./area under the blood concentration vs. time curve in the femoral vein (AUCs)] varied between 27 and 32 ml X kg-1 X min-1. As expected, the Clo (doseo/AUCs) was considerably higher and ranged from 89 to 147 ml X kg-1 X min-1. The Cli (dosei.v./AUChv) was in the same range as Clo (46-163 ml X kg-1 X min-1). The determined oral availability was 19 to 31% with a mean of 25.(ABSTRACT TRUNCATED AT 250 WORDS)