FACTORS AFFECTING METABOLISM OF DRUGS:
As indicated earlier, drug therapy is becoming oriented more to controlling metabolic, genetic, and environmental illnesses (such as cardiovascular diseases, mental illnesses, cancer, and diabetes) than to short term therapy associated with infectious diseases. In most cases, drug therapy lasts for months or even years and the problems of drug toxicity from long term therapy become more serious. Therefore, a greater knowledge of drug metabolism is becoming essential. Several factors influencing xenobiotic metabolism include.
Thus, each of these phenotypic sub-groups experience different responses to drugs extensively metabolized by the CYP2D6 pathway ranging from severe toxicity to complete lack of efficacy. For example, ethnic specificity has been observed with the sensitivity of the Japanese and Chinese to ethanol as compared to Caucasians; CYP2C19 polymorphism (affects about 20% Asians and 3% Caucasians) and the variable metabolism of Omeprazole (proton pump inhibitor) and antiseizure drugs; and the polymorphic paraoxonase (PONI) catalyzed hydrolysis of the neurotoxic organophosphates and of lipid peroxides (atherosclerosis).Polymorphism is a difference in DNA sequence found at 1% or higher in a population and expressed as an amino acid substitution in the protein sequence of an enzyme, resulting in changes in its rate of activity or affinity. Thus, mutant DNA sequences can lead to inter-individual differences in drug metabolism.
Genetic factors :
Pharmacogenetic focuses primarily on genetic polymorphism (mutations) responsible for inter individual differences in drug metabolism and disposition. Genotype-phenotype correlation studies have validated that inherited mutations result in two or more distinct phenotypes causing very different responses following drug administration. The genes encoding for CYP2A6, CYP2C9, CYP2C19 and CYP2D6 are functionally polymorphic, therefore at least 30% of CYP450 dependent metabolism is performed by polymorphic enzymes. For example, mutations in the CYP2D6 gene result in poor, intermediate, or ultra-rapid metabolizes of more than 30 cardiovascular and CNS drugs.
The reality of drug therapy is that many drugs do not work in all patients. By current estimates the percentage of patients who will react favorably to specific drug ranges from 2% to 80%. Drugs have been developed and dosage regimens prescribed under the old paradigm that “one dose fits all” which largely ignores the fact that humans are genetically different, resulting in inter-individual differences in drug metabolism and disposition. It is widely accepted that genetic factors have an important impact on the oxidative metabolism and pharmacokinetics of drugs. Genotype-phenotype correlation studies (pharmacogenetics) have shown that inherited mutations in CYP450 genes (allelles) result in distinct phenotype-subgroups. For example, mutations in the CYP2D6 gene result in poor (PM), intermediate (or extensive, EM), and ultra rapid (UM) metabolizers of CYP2D6 substrate. Each of these phenotypic subgroups experience different responses to drugs extensively metabolized by the CYP2D6 pathway, ranging from severe toxicity to complete lack of efficacy. Genetic studies confirm that “ one dose does not fit all” leaving the question of why we would continue to develop and prescribe drugs under the old paradigm.
Metabolic polymorphism may have several consequences, e.g., when enzymes that metabolize that are used either therapeutically or socially are deficient, adverse or toxic drug reactions may occur in these individuals. The discovery of Genetic Polymorphism resulted from the observation of increased frequency of adverse effects or no drug effects after normal doses of drugs to some patients, e.g., hyper CNS response from the administration of the antihistamine, doxylamine or no analgesic response with codeine.
Furthermore, the Genetic Polymorphisms do not occur with equivalent frequency in all racial or ethnic groups. Because of these differences, it is important to be aware of a person’s race and ethnicity when drugs are metabolized differently by different populations.
Metabolic polymorphism may have several consequences, e.g., when enzymes that metabolize that are used either therapeutically or socially are deficient, adverse or toxic drug reactions may occur in these individuals. The discovery of Genetic Polymorphism resulted from the observation of increased frequency of adverse effects or no drug effects after normal doses of drugs to some patients, e.g., hyper CNS response from the administration of the antihistamine, doxylamine or no analgesic response with codeine.
Furthermore, the Genetic Polymorphisms do not occur with equivalent frequency in all racial or ethnic groups. Because of these differences, it is important to be aware of a person’s race and ethnicity when drugs are metabolized differently by different populations.
Physiologic Factors:
Age is a factor because the very young and the old have impaired metabolism. Hormones (including those induced by stress), sex differences, pregnancy, changes in the intestinal microflora, diseases (especially those involving the liver), and nutritional status can also influence drug and xenobiotic metabolism.Sex Differences:
The rate of metabolism of xenobiotic also varies according to sex in some animal species. For example, 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.g. N-demethylation of aminopyrine, hexobarbital oxidation, glucuronidation of o-aminophenol). Sex differences in drug metabolism appear to be species dependent. Rabbits and mice, for example, do not show a significant sex difference in drug metabolism. In humans, there have been a few reports of sex differences in metabolism. For instance, nicotine and aspirin seem to be metabolized differently in men and women. The role of gender as a contributor to variability in xenobiotic metabolism is not clear, but increasing numbers of reports show differences in metabolism between men and women, raising the intriguing possibility that endogenous sex hormones, or hydrocortisone, or their synthetic equivalents may influence the activity of inducible CYP3A. For example, N-demethylation of erythromycin was significantly higher in females than males. Nevertheless, N-demethylation was persistent throughout adulthood. In contrast, males exhibited unchanged N-demethylation values.
Gender-dependent differences of metabolic rates have been detected for some drugs. Side chain oxidation of propranolol was 50% faster in males than in females, but no differences between genders were noted in aromatic ring hydroxylation. N-demethylation of meperidine was depressed during pregnancy and for women taking oral contraceptives. Other examples of drugs cleared by oxidative drug metabolism more rapidly in men than women included chlordiazepoxide and lidocaine. Diazepam, prednisolone, caffeine, and acetaminophen are metabolized slightly faster by women than by men. No gender differences have been observed in the clearance of phenytoin, nitrazepam, and trazodone, which interestingly are not substrates for the CYP3A subfamily. Gender differences in the rate of glucuronidation have been noted.
Metabolism in the Elderly:
Drug therapy in the elderly has become one of the more significant problems in clinical medicine. It is well documented that the metabolism of many drugs and their elimination is impaired in the elderly.
The decline in drug metabolism because of advanced age is associated with physiologic changes that have pharmacokinetic implications affecting the steady-state plasma concentrations and renal clearance for the parent drug and its metabolites.
Age related changes in drug metabolism are complicated interplay between age-related physiologic changes, genetics, environmental influences (diet and nutritional status, smoking, and enzyme induction), concomitant disease states, and drug intake. In most studies, the elderly appear as responsive to drug metabolizing activity (phase 1) as young individuals. All of the common phase 2 pathways of drug conjugation, including glucuronidation, sulfonation, and glycine conjugation, are variably affected by aging.
A decrease in hepatic drug metabolism coupled with age-related alterations in clearance, volume of distribution, and receptor sensitivity can lead to prolonged plasma half life and increased drug toxicity.
Fetal Metabolism:
The ability of the human fetus and placenta to metabolize drugs and xenobiotics is well established. The knowledge of the effects of prenatal exposure to drugs, environmental pollutants (e.g., smoking) and other xenobiotics (e.g. ethanol) on the fetus has lead to a decrease in the exposure to these substances during pregnancy. The human fetus is at risk from these substances because of the presence of only the cytochrome P450 monooxygenase 3A subfamily, which is capable of metabolizing xenobiotics during the first part of gestation.
Neonatal Metabolism:
From birth, the neonate is exposed to drugs and other foreign compounds persisting from pregnancy as well as those transferred in breast milk. Fortunately, many of the drugs metabolizing enzymes operative in the neonates develop during the fetal period. The routine use of therapeutic agents during labor and delivery and during pregnancy is widespread, and the fact that potentially harmful metabolites can be generated by the fetus and newborn warrants consideration. Consequently, the use of drugs that are capable of forming reactive metabolic intermediates should be avoided during pregnancy, delivery, and the neonatal period. There is evidence of increased activity of drug- metabolizing enzymes in liver microsomes of neonates resulting from treatment of the mother during the pregnancy with enzyme inducers (e.g. phenobarbital).
First pass metabolism:
Although hepatic metabolism continues to be the most important route of metabolism for xenobiotics and drugs, other biotransformation pathways play a significant role in the metabolism of these substances. Among the more active extrahepatic tissues capable of metabolizing drugs are the intestinal mucosa, kidney, and lungs. The ability of the liver and extrahepatic tissues to metabolize substances to either pharmacologically inactive or bioactive metabolites before reaching systemic blood levels is called the pre-systemic first pass effect.
Fetal Metabolism:
The ability of the human fetus and placenta to metabolize drugs and xenobiotics is well established. The knowledge of the effects of prenatal exposure to drugs, environmental pollutants (e.g., smoking) and other xenobiotics (e.g. ethanol) on the fetus has lead to a decrease in the exposure to these substances during pregnancy. The human fetus is at risk from these substances because of the presence of only the cytochrome P450 monooxygenase 3A subfamily, which is capable of metabolizing xenobiotics during the first part of gestation.
Neonatal Metabolism:
From birth, the neonate is exposed to drugs and other foreign compounds persisting from pregnancy as well as those transferred in breast milk. Fortunately, many of the drugs metabolizing enzymes operative in the neonates develop during the fetal period. The routine use of therapeutic agents during labor and delivery and during pregnancy is widespread, and the fact that potentially harmful metabolites can be generated by the fetus and newborn warrants consideration. Consequently, the use of drugs that are capable of forming reactive metabolic intermediates should be avoided during pregnancy, delivery, and the neonatal period. There is evidence of increased activity of drug- metabolizing enzymes in liver microsomes of neonates resulting from treatment of the mother during the pregnancy with enzyme inducers (e.g. phenobarbital).
Pharmacodynamic Factors:
Dose, frequency, and route of administration, plus tissue distribution and protein binding of the drug, affect it’s metabolism.Environmental Factors:
Competition of ingested environmental substances with other drugs and xenobiotics for the metabolizing enzymes and poisoning of enzymes by toxic chemicals, such as CO or pesticides synergists, alter metabolism. Induction of enzyme expression (the number of enzyme molecules increased but activity is constant) by other drugs and xenobiotics is another consideration. Species differences in response to xenobiotics must be considered in the extrapolation of pharmacologic data from experiments in animals to humans. The primary factors in these differences are probably the rate and pattern of drug and xenobiotic metabolism in the various species.First pass metabolism:
Although hepatic metabolism continues to be the most important route of metabolism for xenobiotics and drugs, other biotransformation pathways play a significant role in the metabolism of these substances. Among the more active extrahepatic tissues capable of metabolizing drugs are the intestinal mucosa, kidney, and lungs. The ability of the liver and extrahepatic tissues to metabolize substances to either pharmacologically inactive or bioactive metabolites before reaching systemic blood levels is called the pre-systemic first pass effect.
Elimination Pathways:
Most drugs and xenobiotics are lipid soluble and are altered chemically by the metabolizing enzymes, usually into less toxic and more water soluble substances, before being excreted into urine (or bile in some cases). The formation of conjugates with sulfates, amino acids, and glucuronic acid is particularly effective in increasing the polarity of drug molecules. The principal route of excretion of drugs and their metabolites is in the urine. Urine is not the only route for excreting drugs and their metabolites from the animal body. Other routes include bile, saliva, lungs, sweat, and milk. The bile has been recognized as a major route of excretion for many endogenous and exogenous compounds. Thiocyanate, the detoxification product of cyanide, is excreted principally in the saliva. Some of the drugs may be excreted into the milk and affect the breast-fed baby.Enterohepatic Cycling of Drugs:
Steroid hormones, bile acids, drugs and their respective conjugated metabolites, when eliminated in the bile, are available for reabsorption from the duodenal-intestinal tract into the portal circulation, undergoing the process of enterohepatic cycling (EHC). Nearly all drugs are excreted in the bile, but only a few are concentrated in the bile. For example, the bile salts are so efficiently concentrated in the bile and reabsorbed from the gastrointestinal tract that the entire body pool recycles several times per day. Therefore, EHC is responsible for the conservation of bile acids, steroid hormones, thyroid hormones, and other endogenous substances. In humans, compounds excreted into the bile usually have a molecular weight greater than 500, whereas with rats, the molecular weight is greater than 325. Consequently, biliary excretion is more common in the rat than in man. Compounds with molecular weight between 300 and 500 are excreted in both urine and bile. Unchanged drug in the bile is excreted with the feces, metabolized by the bacterial flora in the intestinal tract, or reabsorbed into the portal circulation.
The impact of EHC on the pharmacokinetics and pharmacodynamics of a drug depends on the importance of biliary excretion of the drug relative to renal clearance and on the efficiency of gastrointestinal absorption. Enterohepatic cycling becomes dominant when biliary excretion is the major clearance mechanism for the drug. Because the majority of bile is stored in the gallbladder and released with the ingestion of food, intermittent spikes in the plasma drug concentration are observed following re-entry of the drug from the bile via EHC. From a pharmacodynamic point of view, the net effect of EHC is to increase the duration of a drug in the body and to prolong it’s duration of action.
Extrahepatic Metabolism:
Because the liver is the primary tissue for xenobiotic metabolism, it is not surprising that our understanding of mammalian CYP450 monooxygenase is based chiefly on hepatic studies. Although the tissue content of CYP450s is highest in liver, CYP450 enzymes are ubiquitous and their role in extrahepatic tissues remains unclear. The CYP450 pattern in these tissues differs considerably from that in the human liver. In addition to liver tissue, CYP450 enzymes are found in lung, nasal epithelium, intestinal tract, kidney and adrenal tissues, and brain. It is possible that the expression of the polymorphic genes and induction of the isoform in the extrahepatic tissues may affect activity of the CYP450 isoforms in the metabolism of drugs, endogenous steroids and xenobiotics.
The mucosal surfaces of the gastrointestinal tract , the nasal passages, and lungs are major portals of entry for xenobiotics into the body and as such are continuously exposed to a variety of orally ingested or inhaled airborne xenobiotics including drugs, plant toxins, environmental pollutants, and other chemical substances. As a consequence of this exposure, these tissues represent a major target for necrosis, tumorigenesis, and other chemically induced toxicities. Many of these toxins and chemical carcinogens are relatively inert substances that must be bioactivated in order to exert their cytotoxicity and tumorigenicity. The epithelial cells of these tissues are capable of metabolizing a wide variety of exogenous and endogenous substances, and provide the principal and initial source of biotransformation for these xenobiotics during the absorptive phase. The consequences of such presystemic biotransformations is either a decrease in the amount of xenobiotic available for systemic absorption by facilitating the elimination of polar metabolites, or toxification by activation to carcinogens, which may be one of the determinant of tissues susceptibility for the development of intestinal cancer. The risk of colon cancer may depend on dietary constituents that contain either procarcinogens or compounds modulating the response to carcinogens. For further detail of extrahepatic metabolism, following topics can be covered. Intestinal metabolism, Lung metabolism, Nasal metabolism and metabolism in other tissues.
Drug interactions:
The clinical importance of any drug interaction depends on factors that are drug, patient and administration related. Drugs with low oral bioavailability or high first pass metabolism are particularly susceptible to drug interactions as a result of co-administration of inhibitors that alter absorption, distribution and elimination. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Drug interactions may be most apparent when patients are stabilized on the affected drug and the CYP450 substrates or inhibitors are then added to the regimen. So by drug interaction induction or inhibition drug metabolism occurs.S tereochemical Aspects of Drug Metabolism:
In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected because the xenobiotic-metabolizing enzymes are also the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity (but not stereospecificity), i.e., one stereoisomer enters into biotransformation pathways preferentially, but not exclusively. Metabolic stereochemical reactions can be categorized as follows.Substrate stereoselectivity:
when two enantiomers of a chiral substrate are metabolized at different rates. An example of substrate stereoselectivity is the preferred de-carboxylation of S-α-methyldopa to S-α-methyldopamine, with almost no reaction for R-α-methyldopa
Product stereoselectivity:
In which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially. The reduction of ketones to stereoisomeric alcohols and the hydroxylation of enantiotropic protons or phenyl rings by monooxygenases are examples of product stereoselectivity. For Example, phenytoin undergoes aromatic
p
-hydroxylation of only one of its two phenyl rings to create a chiral center at C-5 of the hydantoin ring, methadone is reduced preferentially to its α-diastereometric alcohol, and naltrexone is reduced to its 6-ß-alcohol.
Substrate-product stereoselectivity:
which have a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers. An example of substrate-products stereoselectivity is the reduction of the enantiomers of warfarin and the ß-hydroxylation of S-α-methyldopamine to (1R:2S)-α-methylnorepinephrine, whereas R-α-methyldopamine is hydroxylated to only a negligible extent.
Although studies on these stereoselective biotransformation of drug molecules are not yet extensive, those that have been done indicate that stereochemical factors play an important role in drug metabolism and , in some cases could account for the differences in pharmacological activity and duration of action between enantiomers.
