Drug Metabolism under Pathological and Abnormal Physiological States in Animals and Man

Abstract

The activity of microsomal drug-metabolizing enzymes is altered by several pathological or abnormal physiological states, such as changes in nutritional status, liver, heart or kidney diseases, hormonal disturbances, pregnancy, tumour-bearing state, adjuvant arthritis, changes in reticuloendothelial system and environmental factors (stress, irradiation, heavy metals). The activities of other metabolic pathways, such as glucuronidation, sulphate conjugation, acetylation and alcohol oxidation are generally affected to lesser extents. Rats are most commonly used in drug metabolism studies, and it is important to know that the activity of most of the microsomal drug-metabolizing enzymes is higher in males than in females through androgen action which is readily impaire drug-metabolizing enzymes in male rats are thus manifested by two mechanisms; one is by impairment of androgen action and the other is by depression of the basic enzymic activity. Therefore, those effects of pathological states, observed only in male rats but not in females, are generally not seen in other species of animals, including man. The effects of starvation, hyperthyroidism, adrenal insufficiency, diabetes and morphine administration are cases where changes in metabolism are due solely to impairment of androgen action. In other pathological cases, those drug-metabolizing enzymes showing sex differences are depressed more markedly in male rats than those showing no clear sex difference. The author therefore recommends the use of female rats in the evaluation of the effects of pathological states on hepatic microsomal drug-metabolizing enzymes. Generally, changes in activity of the hepatic enzymes reflect closely the changes in the rates of drug metabolism in vivo. However, the protein-binding of drugs, hepatic blood flow and renal function are also known to affect the rate of drug metabolism and excretion in vivo, and therefore changes of these factors in pathological states should also be taken into consideration.

Absence of Changes in Drug Disposition and Catecholamine Sensitivity in the Hyperthyroid Dog

“…In the dog, Vesell et al (1973) found a good inverse correlation between antipyrine T, and the activity of hepatic microsomal aniline hydroxylase and ethylmorphine N-demethylase whereas in man Davies, Thorgeirsson, Breckenridge & Orme (1973) were unable to demonstrate a correlation between antipyrine clearance and the rate of N-demethylation of the ethylmorphine in vitro. Furthermore, in vivo and in vitro studies in laboratory animals suggest that thyroid hormone may inhibit the N-demethylation of aminopyrine (Kato & Gillette, 1965;Kato, 1977). Brunk et al (1974) found no change in dipyrone metabolism when liothyronine was given to eight normal subjects and observed that in the hyperthyroid subject, plasma dipyrone levels were normal and the urinary excretion of 4-aminoantipyrine was decreased.…”

“…Thirdly, since the phenobarbitone treatment did not distort the elimination kinetics of propranolol, a drug interaction between barbiturate and propranolol seems unlikely. Finally, since the available data so far do not allow a general statement about drug disposition and since various pathways and substrates are apparently affected in different ways by thyroid dysfunction (Eichelbaum, 1976;Kato, 1977), each drug must be studied individually in thyroid disorders. Furthermore, the disposition data of certain drugs obtained from artificially-induced hyperthyroidism of an animal species as in this study may not be directly applicable to those in the spontaneously occurring human hyperthyroid state.…”

“…Studies in laboratory animals (Kato & Gillette, 1965;Kato, 1977;Rumbaugh, Kramer & Colby, 1978) have shown that thyroid hormones are among the many endocrine factors which influence the activity of hepatic microsomal drug-metabolizing enzymes. Furthermore, in a number of clinical investigations (Eichelbaum, Bodem, Gugler, SchneiderDeters & Dengler, 1974;Vesell, Shapiro, Passananti, Jorgensen & Shively, 1975;Saenger, Rifkind & New, 1976), hyperthyroidism has been shown to accelerate drug clearance whereas hypothyroidism increases the plasma half-life of drugs.…”

Antipyrine Metabolism in Anorexia Nervosa

“…The pharmacokinetic calculations taking into account body weight suggest, however, that the over-all metabolism of antipyrine is normal in anorexia nervosa. The effect of starvation and restricted feeding on drug metabolism is complex both in animals and in man (Kato, 1977). Significant sex differences exist in that the activity of some NADPH-dependant enzymes in the liver microsomes is depressed in male rats and stimulated in female rats after starvation.…”

“…Nutritional and endocrine factors influence the disposition of many drugs which are metabolized by the liver (Eichelbaum, 1976;Kappas, Anderson, Conney & Alvares, 1976;Stevenson, 1977;Kato 1977). Grave malnutrition and hypometabolism associated with low concentrations of triiodothyronine and thyroxine in plasma and decreased metabolism of cortisol are prominent features of anorexia nervosa (Boyar, Hellmann, Roffward, Katz, Zumoff, O'Connor, Bradlow & Fukushuma, 1977).…”