R. Olavi Pelkonen

Relationship between in vivo and in vitro drug metabolism in man

SummaryRelationship between in vivo and in vitro drug metabolism was investigated in 200 consecutive patients with diagnostic liver needle biopsy by comparing the cytochrome P-450 (P-450) content in biopsies with the elimination kinetics of antipyrine. P-450 level in livers varied from 0.5 to 32.5 nmole/g, it was increased in subjects treated with enzyme inducing drugs and reduced in patients with degenerative parenchymal changes in the liver. Antipyrine metabolism also varied markledy, the half-life ranged from 2.2 to 54.4 hrs and the clearance from 3.5 to 142.4 ml/min. Rapid drug metabolism was associated with subjects with normal liver or with slight liver changes in case they were also treated with known inducers whereas reduced antipyrine metabolism was seen in subjects with degenerative liver changes. P-450 content in biopsies was related to the kinetic parameters of antipyrine: correlation between P-450 in livers and the drug clearance was linear whereas a non-linear relationship between P-450 and plasma half-life was obtained. The results demonstrate a relationship between in vivo and in vitro parameters of drug metabolism in man and show the importance of liver parenchymal changes and drug therapy as factors influencing hepatic drug metabolism.

Impairment of drug metabolism in patients with liver cancer

Abstract. Drug metabolizing capacity was investigated in sixteen patients with cancer in the liver by comparing in vivo (antipyrine disappearance rate from plasma) and in vitro (cytochrome P‐450, benzpyrene hydroxylase, and 7‐ethoxycoumarin O‐deethylase activities in liver biopsies) indices of drug metabolism with the condition of tumour‐free liver parenchyma and with biochemical liver function tests. Drug metabolism was impaired as antipyrine hydroxylation was significantly lower than in matched controls. Impairment of antipyrine metabolism was related to the pathological changes in the liver; patients with metastatic liver cancer or with tumour and cirrhosis metabolized antipyrine at a reduced rate, whereas those with a hepatoma occupying from 20 to 80% of the liver volume had normal antipyrine metabolism. Liver enzyme activities were related to the site of the biopsy; values were low in and around the tumour tissue and high in normal parenchyma. The antipyrine half‐life was related to serum albumin concentration but not to other liver function tests. The results demonstrate that in liver cancer patients the drug‐hydroxylating capacity is dependent on the ability of the tumour‐free parenchyma to metabolize drugs. Hence quantitative evaluation of liver changes together with tests measuring liver synthetic capacity might be of significance when predicting drug metabolism in patients with hepatic malignancy.

Plasma clearance of propranolol and sotalol and hepatic drug-metabolizing enzyme activity

The role of hepatic drug‐metabolizing enzyme activity for plasma propranolol and sotalol levels was investigated in 68 patients with hypertension or angina pectoris by comparing elimination rate with antipyrine kinetics and cytochrome P‐450 content in the liver. All subjects were resistant to or had hepatotoxic reaction to previous treatment. Plasma antipyrine clearance and cytochrome P‐450 content in biopsies were related to propranolol elimination from plasma, the best fit being obtained with the clearance values. Sotalol plasma clearance was not related to any indirect or direct reflector of the hepatic drug‐metabolizing enzyme system. The results demonstrate that plasma clearance of the short‐acting beta blocker, propranolol, depends on the activity of hepatic drug‐metabolizing enzyme system and indicates a trial with a drug such as sotalol which is not dependent on liver metabolizing capacity.

Fibrotic process and drug metabolism in alcoholic liver disease

The effect of fibrosis on drug metabolism in alcoholic liver disease was evaluated in a comparison of the concentrations of serum aminoterminal propeptide of type III procollagen and basement membrane (BM; 7S domain of type IV collagen and laminin) antigens with in vitro (cytochrome P‐450) and in vivo (antipyrine) drug metabolism in 67 alcoholics classified by liver histology. Alcoholics with intact or fatty liver had rapid or normal drug metabolism and normal collagen metabolism. Alcoholics with a fatty liver plus fibrosis or active cirrhosis had reduced drug metabolism and elevated levels of serum markers for collagen and BM metabolism. Alcoholics with inactive cirrhosis who had received therapy with enzyme inducers had a tendency toward normal drug and collagen metabolism parameters. Antipyrine metabolism, but not P‐450 content, was related to the levels of serum type III collagen and BM markers. The fibrotic process, especially BM formation, creates a mechanical barrier that may prevent contact between blood and hepatocytes, thus delaying substrate availability.

Treatment of alcoholic cirrhosis with enzyme inducers

The efficacy of hepatic enzyme–inducing drugs in improving liver function and drug metabolism was investigated in 18 chronic alcoholics with cirrhosis. Five subjects treated continuously with the inducing drugs, phenytoin or prednisolone, for concomitant diseases showed more rapid metabolism than the other patients. Phenobarbital (PB) and medroxyprogesterone acetate (MPA), both known inducers, improved drug metabolism in patients with normal or decreased serum albumin. Serum albumin levels rose in alcoholics with low pretherapy levels, whereas serum albumin in subjects with normal pretherapy levels did not change. Serum thrombotest levels rose in six of seven subjects with low pretreatment values. There was a trend toward normal conventional liver tests during the experiment. There was a relationship between in vivo and in vitro drug metabolism in the alcoholics with cirrhosis. Our results demonstrate that by activating liver function, enzyme‐inducing drugs may be of therapeutic value in alcoholics with liver cirrhosis and hepatic failure.

Relationship Between Lipid Composition and Drug Metabolizing Capacity of Human Liver

SummaryThe relationship between hepatic glycerolipids and microsomal drug-metabolizing enzymes was studied in liver biopsies from 41 subjects. The series included obese, diabetic, epileptic and chronic alcoholic patients, all of whom were hospitalized for suspected hepatic ailments (fatty liver, hepatitis or cirrhosis). Therapy with enzyme-inducing anticonvulsants was associated with high phospholipid and cytochrome P-450 and low triacylglycerol concentration in the liver. In patients with fatty liver or cirrhosis low phospholipid and cytochrome P-450 and high triacylglycerol concentrations were observed. There was a significant correlation (r (Pearsonss product moment correlation coefficient) =0.91) between the hepatic phospholipid and cytochrome P-450 concentration. The cytochrome P-450 concentration was inversely related (r=−0.74) to the triacylglycerol concentration. The positive correlation between hepatic phospholipids and drug-metabolizing enzymes could be interpreted as indicating that in human liver phospholipid and cytochrome P-450 synthesis share common regulators, or that phospholipids are necessary for the maximum rate of cytochrome P-450 synthesis.

Effect of Liver Function on β-Blocker Kinetics

SummaryThe role of the liver on the kinetics of β-blockers metabolised by hepatic enzyme systems (propranolol) or eliminated unchanged (atenolol and sotalol) was investigated in 55 patients with diagnostic liver biopsy, who also required β-blockers for cardiovascular diseases. Microsomal enzyme activity assay in vivo (antipyrine) and in vitro (cytochrome P-450 content), and conventional liver tests were used to reflect liver function in subjects classified by histology.Plasma levels and clearance rate of propranolol, but not of atenolol and sotalol, were related to liver changes, rate of antipyrine elimination and cytochrome P- 450 content. Subjects with reduced serum albumin metabolised propranolol slowly but the values of other liver function tests were not useful when predicting the elimination rate of the β-blockers. The findings show that the kinetics of β-blockers eliminated unchanged are independent of the liver and these drugs are hence recommendable for patients with activated, impaired or with time- altering liver metabolism.

Influence of liver size on the relationship between in vivo and in vitro studies of drug metabolism

SummaryOne hundred and twelve subjects were investigated to elucidate the influence of liver size on the relationship between in vivo (antipyrine kinetics) and in vitro (cytochrome P-450) studies of drug metabolism. The correlation between these variables appeared to be linear in 20 subjects with normal parenchyma and nonlinear in 92 subjects with slight or severe histological alterations in liver biopsy specimens. When liver size was taken into account by calculating the total amount of cytochrome P-450/liver (liver weight g x cytochrome P-450 concentration nmol/g), the relationship between in vivo and vitro studies improved in normal controls. In subjects with changed liver structure the correlation showed no improvement and remained nonlinear.