Metabolism and Pharmacokinetics Flashcards
main organ involved in drug metabolism is
the liver
main route of drug conjugation is by
glucuronidation
metabolism can be divided into
two phases
phase 1 metabolism involves
- oxidation
- reduction
- hydrolysis
which leads to activation/inactivation of drug
phase 2 metabolism involves
conjugation/glucurodination which produces conjugation products
what is family of enzymes are responsible for the majority of drug oxidation
cytochrome p450
cytochrome p450 consists of
a number of isozymes with differing substrate specificity and regulatory mechanisms
Drug metabolism =
biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic activity.
water-soluble substances undergo
excretion
lipid soluble substances are
passively reabsorbed from renal or extra renal excretory sites back into the blood
where are drugs metabolised
- LIVER,
- lining of the gut
- the kidneys
- the lungs.
where are drugs metabolised
- LIVER,
- lining of the gut
- the kidneys
- the lungs.
Purpose of metabolism:
- to increase water solubility and so aid excretion
- to deactivate compounds (may involve a number of steps).
what are prodrugs
drugs that are activated following metabolism.
prodrug example
- codeine
- enalapril
- simvastatin
- sacubitril
Production of toxic metabolites can cause
- direct toxicity
- carcinogenesis
- eratogenesis
Effects of Metabolism
- production of toxic metabolites
- loss of pharmacological activity
- decrease in activity with metabolites that show some activity
- increase in activity, more active metabolites
- prodrug activation
enzymes that are divided into families or subfamilies have
wide substrate specificity and one drug can be metabolised more than one enzyme
phase one metabolism steps
- polar groups are exposed to introduced to a molecule
- involves hydrolysis, oxidation or reduction
- this increases the polarity of compound and provides active site for phase 2 metabolism
cytochrome p450 and isoforms involved in oxidative drug metabolism
CYP1A2 = theophylline
CYP2D6 = codine
CYP3A4 - cyclosporin
relative drug specificity is determined by
isoform of cytochrome p450
major constitutive enzyme in human liver
CYP3A4 = cyclosporin
- contributes to the metabolism of a wide range of drugs
- also found in the gut and is responsible for the pre-sysytemic metabolism of several drugs.
responsible for the metabolism of some antidepressants, antipsychotics
CYP2D6 = codeine
- converts codeine into morphine
- Induction by cigarette smoking may be important in psychiatric patients
- 5-10% of the population may be immune to the analgesic actions of codeine
important in the metabolism of theophylline
CYP1A2 = theophylline
- induced by smoking
- smokers require higher dose than non smokers
conjugation increases
water solubility and enhanced excretion of metabolised compound.
conjugation involves
attachment of
conjugation involves
attachment of glucuronic acid, glutathione, sulphate or acetate into metabolite generated by phase 1 metabolism
conjugation usually results in
inactivation but a small number of rug metabolites may be active.
in phase 2 metabolism a molecule endogenous
to the body donates a portion of itself to the foreign molecule.
Factors Which Affect Metabolism
- Other drugs/herbals/natural substances
- Genetics
- Hepatic blood flow
- Liver disease
- Age
- Sex
- Ethnicity
- Pregnancy
Induction of an enzyme involves
increased synthesis and therefore increased activity.
- The most common enzyme inducers include alcohol and smoking.
-
Many commonly used drugs herbal medicines and food stuffs may
conversely inhibit drug metabolising enzymes.
- May be reversible or irreversible binding to the enzyme.
eg - grapefruit, cimetidine, erythromycin
Grapefruit Juice Increases
Felodipine Oral Availability in Humans by Decreasing Intestinal CYP3A Protein Expression
Lack or decreased activity of an enzyme often results in
increased drug toxicity.
Dose adjustments are required for
drugs in individuals who have the mutant enzymes
Drug metabolising enzymes are often deficient or reduced in
the fetus 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
Hormonal changes during development have a profound effect on
drug metabolism
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
Metabolism is an important process in
eliminating drugs from the body.
