chemistry

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Several Factors Affect Drug Metabolism

Factors affecting metabolism

There are several factors that can affect drug metabolism. Age, sex, inducers and inhibitors are some of which can effect drug metabolism which are mentioned below.

How does age affect drug metabolism:

There are many physiological changes that occur with ageing. The changes have the potential to affect both drug disposition and metabolism. Drug metabolism is mainly functioned by the liver, its size, blood perfusion and synthetic capacity for proteins which all determine the rate of hepatic drug elimination.

Paediatric population

Phase one and phase two metabolic pathways may not be active at birth due to maturational changes. The paediatric population and elderly population have differences in their capacity to metabolise a drug which can therefore produce a lower or higher plasma concentration of active substances compared with adults depending on the enzyme system used. There are examples of metabolites produced by therapeutic agents in children that are not usually seen in adults. The metabolites produced maybe the reason for some of the efficacy and or toxicity visible with drug administration in children. An example is: caffeine production in a neonate receiving Theophylline. Other therapeutic agents which show changes in metabolite production in children are;

  • Valproic acid,

  • paracetamol,

  • Chloramphenicol,

  • Cimetidine

  • Salicylamide.

In most cases the differences that occur between children and adults are in the ratios of the metabolites relative to the parent drug rather than in new metabolites individual to the paediatric population with some exceptions. The paediatric population shows the same set of enzymes as the adult population.

In general age related changes in drug metabolism have been shown to occur due to a consequence of diminished enzyme activities within the elderly human liver due to the size of the liver decreasing and hepatic blood flow decreasing. With age the liver blood flow is generally reduced by about 20-30% and there is a decrease in liver size by about (17-36%).

Currently there is no clear pattern; however there are two general trends that influence the rate of metabolism. One trend is that drugs that are undergoing hepatic microsomal oxidation are more likely to be metabolised slowly in the elderly and those which are conjugated are not likely to be influence by the age factor. Secondly, drugs that have high hepatic clearance, extraction ratios example -Chlormethiazole, and Labetalol and undergo extensive first pass metabolism whilst oral absorption may show a large increase in bioavailability in the elderly.

Elderly population

In general in the elderly population hepatic blood flow decreases up to 40% and there can be a considerable reduction in the amount of drug reaching the liver per unit. Studies have shown that the effect of ageing on liver enzymes with particular drug that are subject to oxidative phase 1 metabolism have decreased elimination. This is due to the fact that phase 1 metabolism is catalyzed by the P450 system in the smooth endoplasmic reticulum of hepatocytes. This process slows down a lot with age. Phase two metabolism is not known to be age associated.

Table 1-A Table to show changes in drug metabolism with Age:

METABOLISM:

Decrease microsomal hepatic oxidation

Decrease in clearance

Increase in steady -state levels

Increase in half lives

Increase levels of active metabolites

Decrease first pass metabolism

As said mentioned before the hemoperfusion of the liver declines in elderly and drugs that have a high extraction show an age related decrease in metabolic clearance as blood which moves via the liver is mostly cleared from these compounds. This is known as blood flow limited metabolism (shown in table 2)In most cases drugs that have low hepatic extraction do not have a reduced metabolic clearance. This is because it is not dependent on hepatic blood flow but instead on the total tissue content of metabolising enzymes. This is called capacity limited metabolism (shown in table 2)

Table 2:A table to show the effect of age on ‘blood flow-limited' or ‘capacity-limited' hepatic drug metabolism with certain drugs (data from [ Le Couteur and Mclean 1998}Le Couteur and McLean, 1998]Le Couteur and McLean, 1998]Le Couteur and McLean, 1998]


Metabolism in old age

Reduced

Unchanged

Blood flow limited metabolism

Amitriptylin

Lidocaine

Pethidine

Verapamil

Morphine

Proprananol

Imipramine

pethidine


Capacity limited metabolism

Antipyrine

theophylline

Diazepam

Digitoxin

Phenytoin

Salicylic acid

Valproic acid

warfarin

How do Sex differences affect drug metabolism?

Another factor that affects drug metabolism is sex differences. Sex differences in pharmokinetics and pharmaco-dynamics characterize many drugs and have effects on individual differences in drug efficacy and toxicity. Sex based differences in drug metabolism are the main cause of sex dependent pharmokinetics. They also reflect underlying changes in the expression of hepatic enzymes active in the metabolism of:

  • Drugs

  • Steroids

  • Fatty acids

  • Environmental chemicals including; cytochrome p450, sulfotransferases, glutathione transferees and UDP-glucuronosyltransferases.

The CYP450 group of enzymes is the main drug metabolizing system used in humans.CYP450 enzymes have shown to have significant sex differences. It has been demonstrated that some major CYP450 enzymes have significant differences depending on gender. As mentioned earlier there are different phases of drug metabolism. Different phases have different enzymes which may have differences in their action depending on their action.

Phase 1 metabolism and gender differences:

CYP1A2 and CYP1A2 enzymes are involved in phase 1 metabolism. They are involved in the clearance of certain medication which includes; Caffeine and Theophylline .There has been experimental data evidence to show that;

  • Theophylline metabolism was faster in men than women.

  • Urinary concentrations of caffeine metabolites revealed lower CYP1A2 activity in women.

  • Antipsychotic agents;Thiothixene,Olanzapine and Clozapine which are all CYP1A2 substrates have a higher clearance in men than women

Females have a predominant expression of CYP3A4 which is one of the most important catalysts of drug metabolism in the liver. There is a lot of evidence that supports that the differences in sex have an impact on these enzymes. Many drug substrates for CYP3A4 have a higher clearance in women. Drugs that have been found to have a higher clearance in women include; Cyclosporine, Erythromycin, Tirilazad, Verapamil, Nifedipine, Diazepam and Alfentanil.

CYP2D6 is the second most frequent enzyme used in the metabolism of therapeutic drugs. Many medications are partially or fully metabolised by CYP2D6;

Examples of drugs metabolised by CYP2D6 and sex differences in their action;

  • Sertraline is a CYP2D26 substrate which is found to be higher in young men compared to females.

  • Oral clearance of Desipramine has been found greater in males compared to females.

  • Mirtazapine is an antidepressant which is metabolised largely by CYP2D6 and CYP3A and has shown to have a faster clearance in men.

(3)Sex differences in phase Two metabolism:

There is some evidence that suggests that there are sex differences in the metabolism of glucuronidation of some therapeutic compounds.

Table 3:A table to show the differences in sex affecting the clearance of substrates in Phase two metabolism:

Hepatic

Model substrate

Clearance

CYP1A2

Caffeine,

Paracetamol

Increase in men

CYP3A4

Midazolam

Nifedipine

Erythromycin

Increase in women

CYP2D6

Dextrometorphan

Debrisoquine

Sparteine

Increase in men

CYP2C9

CYP2C19

(s)-Mephenitoine

No sex differences



CYP2E1

Transporter hepatic P-gp

Chlorzoxazone

Increase in men

Increase in women

Inducers affecting drug metabolism:

This is the process where enzyme activity is enhanced due to increased enzyme synthesis. An e.g. of this is Rifampicin selectivity induces CYP384.The group of P450 isoform shows great selectivity of induction. Enzyme induction has a practical consequence, in that when two or more drugs are given simultaneously, the inducer speeds up the drug metabolism of other drugs. Examples of drugs which cause enzyme induction are: Rifampicin, Carbamazepine, Ethanol and Phenobarbitone.

Inhibitors:

There are many drugs that exert their therapeutic effect by enzyme inhibition Example: Methrotrexate, Angiotensin converting enzyme inhibitors ,non-steroidal anti-inflammatory drugs).inhibition of drug metabolism by a concurrently administered drug eventually can cause drug accumulation and toxicty. Certain inhibitors have selectivity for p450 isoforms, an example is- Ketoconazole in comparison to example- Cimetidine which inhibit all cytochrome p450-mediated metabolis. Both the drugs both of the drugs warfarin and Phenytoin compete with each other in their metabolism when given together. This results in the increase of drug concentration in plasma of both drugs. Examples of drugs which inhibit cytochrome p450: Cimetidine, Erythromycin, Ciprofloxacin, Isoniazid and Chloramphenicol.


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