The Possible Role of Cytochrome P‐450 in the Liver “First Pass Elimination” of a P‐Receptor Blocking Drug

Abstract

The highly lipid soluble β‐receptor blocking drug alprenolol interacts with high affinity with rat liver microsomal cytochrome P‐450, is rapidly metabolized in the liver and exhibits a marked liver “first pass elimination” (FPE) in the rat. It thus has a low oral bioavailability in this species. In order to investigate the possible role of the cytochrome P‐450 system in the FPE we studied the influence of the three P‐450 inhibitors SKF 525‐A, imipramine and metyrapone and of phenobarbital treatment on the disposition kinetics of alprenolol in a series of experimental models. Alprenolol rapidly gave rise to a type I spectral change on addition to intact liver cells, indicating a rapid hepatic uptake. The maximal magnitude of this spectrum increased about twofold after phenobarbital treatment of rats in both microsomes and isolated liver cells. Imipramine, SKF 525‐A and metyrapone partly displaced 3 H‐al‐prenolol from non‐metabolizing partly purified cytochrome P‐450 and liver cell preparations (20°). Imipramine and SKF 525‐A were about equally effective in this respect whereas metyrapone was much less potent. At 37° the metabolism of alprenolol was rapid and of about similar activity (per nmoles of cytochrome) in liver microsomes, isolated liver cells and in the perfused liver (at a high dose). The K m ‐value was similar in microsomes and in isolated liver cells. A similar metabolic inhibitory pattern was found in microsomes and isolated liver cells. SKF 525‐A was the most efficient inhibitor followed by imipramine and then metyrapone. The same inhibitory pattern was found for the hepatic extraction of alprenolol. Moreover, the hepatic extraction of alprenolol was dose dependent. Imipramine in a high dose increased the area under the blood concentration curve by a factor of ten after oral administration of alprenolol in the conscious rat. The above findings suggest that cytochrome P‐450 is, at least partly, responsible for the degree of hepatic extraction and metabolism (FPE) of alprenolol. This view was also supported by the findings that the perfused liver showed an increased capacity for the extraction and metabolism of alprenolol after phenobarbital treatment. The cytochrome P‐450 system may influence the hepatic extraction of alprenolol in rat liver by providing an intracellular “high affinity binding pool” for the unchanged drug. The subsequent metabolic step seems to be important since it “unloads” P‐450 so that it can bind new drug molecules.