drug metabolism Flashcards
define drug metabolism
biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic activity
which substances undergo excretion
only water soluble ones
lipid soluble are passively reabsorbed from renal or extra renal accessory sites back into the blood
important sites of metabolism
liver
gut lining
kidneys
lungs
what is the purpose of metabolism
increase water solubility and so aid excretion
deactivate compounds
- some drugs are activated (prodrugs)
what is a prodrug
inactive until they are metabolised in the liver e.g. codeine
effects of metabolism
loss of pharmacological activity
decrease in activity
increase in activity - prodrugs
production of toxic metabolites
production of toxic metabolites can cause …
direct toxicity
carcinogenesis
teratogenesis
terfenadine
inactive terfenadine is converted to its active metabolite fexofenadine
enzymes
there are numerous metabolising enzymes
they often have wide substrate specificity
enzyme control is regulated at several levels
some enzymes are expressed constitutively
others are expressed or induced in the presence of . particular substrate
phase 1 reactions
convert the drug into a more reactive species which can then be conjugated in phase 2
what are the 3 processes in phase 1 reactions
oxidation
reduction
hydrolysis
phase 1 reactions - exposing or introducing polar groups onto molecules
involves hydrolysis, oxidation or reduction
increases polarity of the compound, provides active site for phase 2 metabolism
cytochrome P450 enzymes are the most important family
drug specificity is determined by …
isoform of cytochrome P450
specificity tends to be relative rather than absolute
phase 2 metabolism - conjugation
involves conjugation
increases water solubility and enhances excretion of the metabolised compound
attachemnet of glucuronic acid, glutathione, sulphate, acetate to the metabolite
usually results in inactivation
factors the affect drug metabolism (8)
other drugs/herbal substances genetics hepatic blood flow liver disease age sex ethnicity pregnancy
enzyme induction
many enzymes involved in drug metabolism can be induced by other compounds
- increased drug metabolism
- decreased drug effect
most common enzyme inducers are alcohol and smoking
also includes drugs and herbals (phenytoin, carbazepine, rifampicin, St Johns wort)
enzyme inhibition
includes commonly used drugs, herbal medicines and foods
can be reversible or irreversible
- cimetidine, valproate, erythromycin, clarithromysin, ketoconazole, CCBs, grapefruit juice
grapefruit juice
increase felodipine oral availability in humans by decreasing intestinal CYP3A protein expression
genetic variation pharmacogenetics
- Wide variability in the response to drugs between individuals
- Consequences of such variation may be therapeutic failure or an adverse drug reaction
- Genetic diversity is the rule rather than the exception with all proteins, including drug metabolizing enzymes
- Drug metabolising enzymes are often expressed in multiple forms (with different levels of activity)
- Therefore inter-individual differences in gene expression are common.
Gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme.
genetic polymorphisms
- Lack or decreased activity of an enzyme often results in increased drug toxicity.
- Less commonly there may be multiple expressions of a particular metabolising enzyme, which may result in enhanced metabolism and reduced drug effect or drug resistance.
Eg – fast/slow acetylators; cholinesterase (suxamethoneum).
CYP2D6 polymorphisms
- Approximately 70 nucleotide polymorphisms are known
- Four phenotype subpopulations of metabolizers
• Poor metabolizers (PM): 6-10% of caucasians
• Intermediate metabolizers (IM)
• Extensive metabolizers (EM): majority of the rest of the pop
• Ultrarapid metabolizers (UM) - may not respond in the expected way to normal doses, 20-30% of S aisian/ethiopian
More than 65 commonly used drugs are substrates
- Metabolizes some 16 commonly used drugs e.g. warfarin and phenytoin
- Two allelic variants are known: metabolizes substrates 5% to 12% of the wild type enzyme
- Warfarin clearance is greatly reduced in individuals possessing the allelic variants
Dose adjustments are required for drugs in individuals who have the mutant enzymes
CYP2C19
- Eight allelic variants identified
- All are nonfunctional proteins
Dose adjustments must be made for poor metabolizers of S-mephenytoin and for other drugs that are substrates for this enzyme
Enzymes that exhibit genetic variation
Pseudocholinesterase
N-Acetyltransferase (isoniazid is a substrate)
• Cytochrome P450 2D6
• Cytochrome P450 2C19
• TMPT -Thiomethylpurinetransferase
• Dihydropyrimidine Dehydrogenase
Patients with low activity (6-10%) or absent activity (0.3%) are at risk of drug-induced bone marrow toxicity
children
• Drug metabolising enzymes are often deficient or reduced particularly in the foetus or premature infant.
• Renal function is also deficient so drug and metabolites rapidly build up to toxic levels.
• By the age of two years children can metabolise many drugs more rapidly than adults.
By puberty the rate of metabolism is greater than that of adults. Rate falls as they become adults.
gender
• Sex-based differences have been found in all four pharmacokinetic areas: Absorption, Distribution, Metabolism, and Elimination.
• Responsiveness to certain drugs is different for men and women
• Pregnancy – induction of certain drug metabolizing enzymes occurs in second and third trimester
Hormonal changes during development have a profound effect on drug metabolism
elderly
• In the elderly parameters such as plasma protein, lean body mass and liver weight decrease significantly and so alter drug metabolism.
Chronic disease is also more common and so the elderly are likely to be on multiple drug therapy
ethnicity
• Race may also affect drug metabolism.
• There are many incidences of racial differences in the genetic expression of cytochrome P-450 isoforms
Results from drug studies in one area may not be generalisable worldwide to other ethnicities
