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 3H‐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 Km‐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.

Extraction and Metabolism of Lidocaine in Rat Liver

“…It binds with an unusually high affinity to liver microsomal cytochrome P-450, and the drug is completely extracted during one passage through the isolated perfused rat liver. These findings are consistent with the hypothesis that a high affinity for cytochrome P-450 is a characteristic property of some drugs that have marked first pass effect in the liver (VON BAHR et al 1972GRUNDIN et al 1974). The fact that 5, which has almost complete oral availability in man (MEYER et al.…”

Kinetic Studies of Dose‐Dependent Metabolism of Alprenolol: In Vitro and In Vivo Studies in Different Species

“…In the same study the microso-ma1 fraction accounts for most of the rat liver binding capacity. It was suggested that cytochrome-P-450 plays an important role in the presystemic elimination in the rat, which was further supported by studies with cytochrome-P-450 inhibitors in in vitro experimental models (Grundin et al 1974). The presence of several different forms of cytochrome-P-450, rather than a single enzyme with multiple catalytic activities has in recent years been demonstrated by a number of investigators e.g.…”

“…Alprenolol is a substrate of the monooxygenase enzyme system in the liver and has a high affinity for cytochrome-P-450 . Based on studies with alprenolol, lidocaine and propranolol, it has been proposed that the presystemic elimination of lipophilic drugs might be due to a cytochrome-P-450-dependent hepatic extraction (Grundin et al 1974). Alprenolol, o-allylphenoxypropanol-isopropylamine is extensively metabo-lized in the rat, dog and man, with aromatic hydroxylation and conjugation with glucuronic acid as the main metabolic pathways (Bodin 1974).…”

The Inhibition of the Mitochondrial NADH Oxidase by Alprenolol and the Protective Effect of Cytochrome P‐450

“…5 suggest that it is probably also of importance for the low inhibitory effect of alprenolol on oxygen uptake in isolated liver cells. Thus, in the presence of SKF 525-A, which interferes with the binding of alprenolol to cytochrome P-450 (GRUNDIN et al 1974), the inhibitory effect of alprenolol on cellular oxygen uptake is markedly increased. It should be added that SKF 525-A, by itself, in the concentrations used, had no effect on the rate of cellular oxygen uptake.…”