The relative amount of any particular metabolite is determined by the concentration and activity of the enzyme s responsible for the biotransformation. The rate of metabolism of a drug is particularly important for its pharmacological action as well as its toxicity. For example, if the rate of metabolism of a drug is decreased, this generally increases the intensity and duration of the drug action.
In addition, decreased metabolic elimination may lead to accumulation of toxic levels of the drug. Conversely, an increased rate of metabolism decreases the intensity and duration of action as well as the drug's efficacy.
Many factors may affect drug metabolism, and they are discussed in the following sections. These include age, species and strain, genetic or hereditary factors, sex, enzyme induction, and enzyme inhibition. In general, the ability to carry out metabolic reactions increases rapidly after birth and approaches adult levels in about 1 to 2 months.
An illustration of the influence of age on drug metabolism is seen in the duration of action sleep time of hexobarbital in newborn and adult mice. In contrast, the adult mouse sleeps for fewer than 5 minutes when given the same dose.
In humans, oxidative and conjugative e. For example, the oxidative CYP metabolism of tolbutamide appears to be markedly lower in newborns. As discussed previously, infants possess poor glucuronidating ability because of a deficiency in glucuronyltransferase activity. The inability of infants to conjugate chloramphenicol with glucuronic acid appears to be responsible for the accumulation of toxic levels of this antibiotic, resulting in the so-called gray baby syndrome.
There is some evidence in animals and humans that drug metabolism diminishes with old age. In evaluating the effect of age on drug metabolism, one must differentiate between "normal" loss of enzymatic activity with aging and the effect of a diseased liver from hepatitis , cirrhosis , etc. Species and Strain Differences The metabolism of many drugs and foreign compounds is often species dependent. Different animal species may biotransform a particular xenobiotic by similar or markedly different metabolic pathways.
Even within the same species, individual variations strain differences may result in significant differences in a specific metabolic pathway. A new drug application requires the developer to account for the product as it moves from the site of administration to final elimination from the body.
It is difficult enough to find appropriate animal models for a disease. It is even harder to find animal models that mimic human drug metabolism. Species variation has been observed in many oxidative biotransformation reactions. For example, metabolism of amphetamine occurs by two main pathways: In human, rabbit, and guinea pig, oxidative deamination appears to be the predominant pathway; in the rat, aromatic hydroxylation appears to be the more important route.
Species differences in many conjugation reactions also have been observed. Often, these differences are caused by the presence or absence of transferase enzymes involved in the conjugative process. For example, cats lack glu-curonyltransferase enzymes and, therefore, tend to conjugate phenolic xenobiotics by sulfation instead.
For example, glycine conjugation is a common conjugation pathway for benzoic acid in many animals. In certain birds e.
However, nonprimates, such as rabbit and rat, excrete phenylacetic acid only as the glycine conjugate. The metabolic product pattern in human or guinea pig does not correlate with that of either rat or mouse Fig.
These differences apparently are caused by genetic variations in the amount of metabolizing enzyme present among the different strains. For example, in vitro studies indicate that cottontail rabbit liver microsomes metabolize hexobarbital about 10 times faster than New Zealand rabbit liver microsomes.
Hereditary or Genetic Factors Marked individual differences in the metabolism of several drugs exist in humans. The frequently cited example of the biotransformation of the antituberculosis agent isoniazid is discussed previously under acylation.
Genetic factors also appear to influence the rate of oxidation of drugs such as phenytoin, phenylbutazone, dicumarol, and nortriptyline. In general, individuals who tend to oxidize one drug rapidly are also likely to oxidize other drugs rapidly.
Numerous studies in twins identical and fraternal and in families indicate that oxidation of these drugs is under genetic control.
It now is realized that their CYP2D6 isozyme does not readily O-demethylate codeine to form morphine. The chemical imbalances seen with some mental diseases may be the cause. Sex Differences The rate of metabolism of xenobiotics also varies according to gender in some animal species.
A marked difference is observed between female and male rats. Adult male rats metabolize several foreign compounds at a much faster rate than female rats e.
Apparently, this sex difference also depends on the substrate, because some xenobiotics are metabolized at the same rate in both female and male rats. Differences in microsomal oxidation are under the control of sex hormones, particularly androgens; the anabolic action of androgens seems to increase metabolism.
Rabbits and mice, for example, do not show a significant sex difference in drug metabolism. For instance, nicotine and aspirin seem to be metabolized differently in women and men.
For women, the focus is on drugs used for contraception. Note in Table 3. Enzyme Induction The activity of hepatic microsomal enzymes, such as the CYP mixed-function oxidase system, can be increased markedly by exposure to diverse drugs, pesticides, polycyclic aromatic hydrocarbons, and environmental xenobiotics. The process by which the activity of these drug-metabolizing enzymes is increased is termed enzyme induction.
Enzyme induction often increases the rate of drug metabolism and decreases the duration of drug action. Inducing agents may increase the rate of their own metabolism as well as those of other unrelated drugs or foreign compounds Table 3. For instance, a clinically critical drug interaction occurs with phenobarbital and warfarin.
Therefore, if a patient is receiving warfarin anticoagulant therapy and begins taking phenobarbital, careful attention must be paid to readjustment of the warfarin dose. Dosage readjustment is also needed if a patient receiving both warfarin and phenobarbital therapy suddenly stops taking the barbiturate. The ineffectiveness of oral contraceptives in women on concurrent phenobarbital or rifampin therapy has been attributed to the enhanced metabolism of estrogens e.