Biological Factors of Drug

BIOLOGICAL FACTORS

Species Differences, 

Strain Differences/Pharmacogenetics, 

Sex Differences, 

Age, 

Diet, 

Altered Physiological Factors, 

Temporal Factors

Species Differences

Screening of new therapeutic molecules to ascertain their activity and toxicity requires study in several laboratory animal species. Differences in drug response due to species differences are taken into account while extrapolating the data to man.

Species differences have been observed in both phase I and phase II reactions. In phase I reactions, both qualitative and quantitative variations in the enzyme and their activity have been observed. An example of this is the metabolism of amphetamine and ephedrine. In men and rabbit, these drugs are predominantly metabolised by oxidative deamination whereas in rats the aromatic oxidation is the major route. In phase II reactions, the variations are mainly qualitative and characterized either by the presence of, or complete lack of certain conjugating enzymes; for example, in pigs, the phenol is excreted mainly as glucuronide whereas its sulphate conjugate dominates in cats. Certain birds utilize ornithine for conjugating aromatic acids instead of glycine.

Strain Differences/Pharmacogenetics

Enzymes influencing metabolic reactions are under the genetic control. Just as the differences in drug metabolising ability between different species are attributed to genetics, so also are the differences observed between strains of the same animal species. A study of inter-subject variability in drug response (due to differences in, for example, rate of biotransformation) is called as pharmacogenetics. The inter-subject variations in drug biotransformation may either be monogenically or polygenically controlled. A polygenic control has been observed in studies in twins. In identical twins (monozygotic), very little or no difference in the metabolism of phenylbutazone, dicoumarol and antipyrine was detected but large variations were apparent in fraternal twins (dizygotic; twins developed from two different eggs) for the same drugs.

Differences observed in the metabolism of a drug among different races are called as ethnic variations. Such a variation may be monomorphic or polymorphic. When a unimodal frequency distribution is observed in the entire population, the variations are called as continuous or monomorphic; for example, the entire human race acetylate PABA and PAS to only a small extent. A polymodal distribution is indicative of discontinuous variation (polymorphism). An example of polymorphism is the acetylation of isoniazid (INH) in humans. A bimodal population distribution was observed comprising of slow acetylator or inactivator phenotypes (metabolise INH slowly) and rapid acetylator or inactivator phenotypes (metabolise INH rapidly) (see Table 5.6.).

TABLE 5.6

Ethnic Variations in the N-Acetylation of Isoniazid

Approximately equal percent of slow and rapid acetylators are found among whites and blacks whereas the slow acetylators dominate Japanese and Eskimo populations. Dose adjustments are therefore necessary in the latter groups since high levels of INH may cause peripheral neuritis. Other drugs known to exhibit pharmacogenetic differences in metabolism are debrisoquine, succinyl choline, phenytoin, dapsone and sulphadimidine.

Sex Differences

Sex related differences in the rate of metabolism could be attributed to regulation of such processes by sex hormones since variations between male and female are generally observed following puberty. Such sex differences are widely studied in rats; the male rats have greater drug metabolising capacity. In humans, women metabolise benzodiazepines slowly than men and several studies show that women on contraceptive pills metabolise a number of drugs at a slow rate.

Age

Differences in the drug metabolic rate in different age groups are mainly due to variations in the enzyme content, enzyme activity and haemodynamics.

^·            In neonates (upto 2 months), the microsomal enzyme system is not fully developed and many drugs are biotransformed slowly; for example, caffeine has a half-life of 4 days in neonates in comparison to 4 hours in adults. A major portion of this drug is excreted unchanged in urine by the neonates. Conjugation with sulphate is well developed (paracetamol is excreted mainly as sulphate) but glucuronidation occurs to a very small extent. As a result, hyperbilirubinaemia precipitates kernicterus and chloramphenicol leads to cyanosis or Gray baby syndrome in new born. Similarly, sulphonamides cause renal toxicity and paracetamol causes hepatotoxicity.

^·            Infants (between 2 months and one year) show almost a similar profile as neonates in metabolising drugs with improvement in the capacity as age advances and enzyme activity increases.

·           Children (between one year and 12 years) and older infants metabolise several drugs much more rapidly than adults as the rate of metabolism reaches a maximum somewhere between 6 months and 12 years of age. As a result, they require large mg/Kg doses in comparison to adults; for example, the theophylline half-life in children is two-third of that in adults.

^·            In very elderly persons, the liver size is reduced, the microsomal enzyme activity is decreased and hepatic blood flow also declines as a result of reduced cardiac output all of which contribute to decreased metabolism of drugs. Drug conjugation however remains unaffected.

Diet

The enzyme content and activity is altered by a number of dietary components. In general –

^·            Low protein diet decreases and high protein diet increases the drug metabolising ability. This is because the enzyme synthesis is promoted by protein diet which also raises the level of amino acids for conjugation with drugs.

^·            The protein-carbohydrate ratio in the diet is also important; a high ratio increases the microsomal mixed function oxidase activity.

^·            Fat free diet depresses cytochrome P-450 levels since phospholipids, which are important components of microsomes, become deficient.

^·            Dietary deficiency of vitamins (e.g. vitamin A, B₂, B₃, C and E) and minerals such as Fe, Ca, Mg, Cu and Zn retard the metabolic activity of enzymes.

^·            Grapefruit inhibits metabolism of many drugs and improve their oral availability.

^·            Starvation results in decreased amount of glucuronides formed than under normal conditions.

^·            Malnutrition in women results in enhanced metabolism of sex hormones.

^·            Alcohol ingestion results in a short-term decrease followed by an increase in the enzyme activity.

Altered Physiological Factors

Pregnancy: Studies in animals have shown that the maternal drug metabolising ability (of both phase I and phase II reactions) is reduced during the later stages of pregnancy. This was suggested as due to high levels of steroid hormones in circulation during pregnancy. In women, the metabolism of promazine and pethidine is reduced during pregnancy or when receiving oral contraceptives. Higher rate of hepatic metabolism of anticonvulsants during pregnancy is thought to be due to induction of drug metabolising enzymes by the circulating progesterone.

Hormonal Imbalance: The influence of sex hormones on drug metabolism has already been discussed. The effect of other hormones is equally complex. Higher levels of one hormone may inhibit the activity of few enzymes while inducing that of others. Adrenolectomy, thyroidectomy and alloxan induced diabetes in animals showed impairment in the enzyme activity with a subsequent fall in the rate of metabolism. A similar effect was observed with pituitary growth hormone. Stress related changes in ACTH levels also influence drug biotransformation.

Disease States: As liver is the primary site for metabolism of most drugs, all pathologic conditions associated with it result in enhanced half-lives of almost all drugs. Thus, a reduction in hepatic drug metabolising ability is apparent in conditions such as hepatic carcinoma, hepatitis, cirrhosis, obstructive jaundice, etc. Biotransformations such as glycine conjugation of salicylates, oxidation of vitamin D and hydrolysis of procaine which occur in kidney, are impaired in renal diseases. Congestive cardiac failure and myocardial infarction which result in a decrease in the blood flow to the liver, impair metabolism of drugs having high hepatic extraction ratio e.g. propranolol and lidocaine. In diabetes, glucuronidation is reduced due to decreased availability of UDPGA.

Temporal Factors

Circadian Rhythm: Diurnal variations or variations in the enzyme activity with light cycle is called as circadian rhythm in drug metabolism. It has been observed that the enzyme activity is maximum during early morning (6 to 9 a.m.) and minimum in late afternoon (2 to 5 p.m.) which was suggested to correspond with the high and low serum levels of corticosterone (the serum corticosterone level is dependent upon the light-dark sequence of the day). Clinical variation in therapeutic effect of a drug at different times of the day is therefore apparent. The study of variations in drug response as influenced by time is called as chronopharmacology. Time dependent change in drug kinetics is known as chronokinetics. Drugs such as aminopyrine, hexobarbital and imipramine showed diurnal variations in rats. The half-life of metyrapone was shown to be 2.5 times longer during the night than in the day, in rats.