Intrinsic factors
- Species:
The rate of metabolism has been proved to vary from species to species. When a drug is administered through same route in humans, monkey, rat and rabbit, the total metabolism was found to be highest in humans and decreased in the same order as above. i.e., the order of metabolism is as follows:
Humans >>> Monkey > Rat > Rabbit
Even in higher plants, the rate of metabolism varies. It was observed that the rate of metabolism in higher plants was also being influenced greatly by the age of different tissues. As an evidence of this statement, caffeine metabolism was observed in the tea leaves of two different ages. The young leaves were reported to synthesize caffeine by utilizing theophylline while aged leaves of Coffea arabica formed 7-methylxanthine accumulation due to further metabolism of caffeine. Hence, it is concluded that metabolism rate and metabolic products differ from species to species.
- Sex:
Initial observations about the differences in drug metabolism both qualitatively and quantitatively in relation to gender has been made in early 1930s. these studies had proved that female rats need only half the dose of barbiturates to induce sleep compared with male rats which later was found that female rats are having less capacity than male rats to metabolize barbiturate.
The basal metabolic rate (BMR) is high in males than in females which enables males to metabolize drugs more efficiently. However, females have an increased rate of metabolism during pregnancy due to which the dose may have to be increased.
- Age:
Its been observed since from the ancient times that newborn, young and elderly show a marked difference in the biotransformation process. Extreme ages i.e., very young and very old will behave almost the same. This happens because, the microsomal and non-microsomal enzymes are different in different age groups. Especially, these enzymes are found deficient in newborn, particularly in premature, which makes them susceptible to many drugs like opioids.
- Pathological status:
Other diseases also affect the way of drug clearance by the body. In these diseases, the primary concern is the diseases affecting the liver as liver is the organ where majority of metabolic reactions takes place. The diseases that affect liver include cirrhosis, cholestatic jaundice, liver carcinoma and alcoholic liver disease. Other diseases/disorders include various types of infections like bacterial and viral and endocrine disorders like thyroidism (both hypo- and hyper-), pituitary disorders and diabetes mellitus. As liver is location for the most important enzymatic systems, when it is infected or affected, the enzyme system especially the CYPs also affected. Studies have been proved that liver diseases resulted in lowering of hepatic P450 which further may lead to renal failure.
- Hormonal control of drug metabolism:
Even hormones being in direct connection with the factors such as age, sex or with particular physiological states like pregnancy also influence drug metabolism. Thyroid status contributes to significant difference for metabolism of different drugs. It has been proved that the rats with hyperthyroidism have shown a marked modulation with an average increase of 5% when compared with normal rats. The hypothalamo-pituitary-liver axis has been proven as a hormonal control system in the drug metabolism as well as in the metabolism of endogenous compounds.
- Enzyme induction:
We all know the importance of enzymes in the metabolism of drugs. We have observed that metabolism process is being catalyzed by various classes of enzymes like CYPs. Enzyme induction is the stimulus which increases the quantity of enzymes. This stimulus may be because of drugs also. The drugs that cause increase in the quantity of enzymes are called as enzyme inducers. With enzyme induction, metabolism and metabolic rate will be increased.
Eg: Phenobarbitone which is used to treat seizures and epilepsy is also an enzyme inducer
- Enzyme inhibition:
Enzyme inhibition is the activity in which the metabolic enzymes are blocked from performing their activity. This may happen by blocking the enzymes from performing their activity or by reducing the availability/quantity of enzymes for the metabolism process.
Eg: Sulfonamides decrease the metabolism of Phenytoin and Cimetidine reduces the metabolism of propranolol.
- First pass metabolism/Route of administration/presystemic metabolism:
When the drugs are administered orally, they undergo first pass metabolism. This is the metabolism of drug molecules in the liver before entering into blood circulation. Maximum amount of the drug is metabolized in the liver before entering into circulatory system (80% of propranolol is metabolized in the liver before entering into circulatory 3system), resulting in less availability of the drugs in the circulatory system i.e., less bioavailability. This can be avoided by changing the route of administration. For example, administering the drug through IV route or sublingual route can bypass the first pass metabolism and hence, results in maximum bioavailability. Hence, route of administration influences drug metabolism.
- Genetic variations:
Genetic difference also influences drug metabolism. Genes varies in different individuals. These genetic variations are seen mostly in non-microsomal enzymes. Because of absent or malformed genes in different individuals, drug molecules behave differently. This variation in genes results in fast or slow metabolism of drugs.
Environmental factors
- Exposure to pollutants:
Pollutants like cigarette smoke, alcoholism, pesticides or insecticides, environmental conditions like hot and humid conditions, high altitudes influence drug metabolism. Conditions like cigarette smoke, chronic alcoholism may act as enzyme inducers which may increase the drug metabolism. Whereas, exposing to climatic conditions like hot and humid conditions, high altitudes decrease the drug metabolism. At high altitudes, availability of oxygen will be very low, resulting in less oxidation of drug molecules. Hence, the metabolism will be less.
- Stereochemical aspects:
Stereochemical aspects include shape, spatial arrangement of the atoms/groups in a molecule and the configuration (+/-, levo-/dextro-, R/S, cis-/trans-) of the molecule. As the receptors in the body is having specific steric arrangement, the drug molecules that fir with the steric features will be having more affinity towards the receptor and may be less metabolized and vice versa. The same will be applicable for enzymes also. The drugs with similar steric features with enzymes will have more affinity towards the enzymes and hence, modification also will be effective.