Pharmacokinetics 2 Flashcards
Metabolism and excretion:
Two major routes of drug elimination :
1.)excretion- from the body as unchanged drugs by the kidneys
2.)hepatic metabolism
Liver- enzymes (cytochrome P-450; CYPs) transform drugs into more water-soluble metabolites
Kidneys-traps water-soluble (ionised) compounds for elimination via urine (primarily)
Excretions other routes:
Lungs- alcohol breath
Breast milk: acidic, alcohol-concentration same as blood and antibiotic
Also bile,skin and saliva. 95% of alcohol is eliminated by hepatic metabolism, the rest in exhaled breathe, urine and sweat
Drug metabolism (biotransformation)
Renders lipid soluble, non-polar compounds to water soluble, polar compounds to enable excretion
It’s a series of enzyme catalysed reactions that change the physiochemical properties of the drug from those favouring movement across biological membranes (lipophilicity) to those favouring elimination in urine or bile (hydrophilicity)
The kidneys can eliminate drugs which are polar and fully ionised at physiological pH and most drugs don’t fit this criteria as they are unionised, partially ionised, lipophilic molecules
Goal of drug metabolism is to transform such compounds into more polar (i.e. more readily excretable) water soluble (hydrophilic) products.
For example, without metabolism, thiopental, a short-acting, lipophilic anaesthetic, would have a half-life of more than 100 years.
Drug metabolism (biotransmission)2:
Most products of drug metabolism are less active than the parent compound.
In some cases, however, metabolites may be responsible for toxic, mutagenic, teratogenic or carcinogenic effects.
Paracetamol in overdose is metabolized to NAPQI which is very toxic, due to covalent bonding to liver proteins leads to severe liver failure
In some cases, with metabolism of so-called prodrugs, metabolites are actually the active therapeutic compounds.
One example of a prodrug is cyclophosphamide, an inert compound which is metabolized by the liver into a highly active anticancer drug.
Another prodrug example is aspirin (acetylsalicylic acid)
Sites of drug metabolism:
The liver is the primary organ of drug metabolism
The gastrointestinal tract is the most important extra hepatic site
Secondary sites of drug metabolism include:
-kidney
-lungs
-testes
-skin
-placenta
Metabolism phases:
Mostly in the liver to convert lipid soluble drugs into water soluble derivatives
Phase 1 metabolism
small structural changes (chemical reaction)
Oxidation
Reduction
Hydrolysis
Phase 2 metabolism
Coupling to large molecules in the body
Glucuronic acid
Glutathione or
Amino acids
Hepatic first pass metabolism
Reduced amount of parent drug
Metabolites
More water soluble - facilitates excretion
Activity
Can decrease drug activity (metabolised to inactive form)
Can increase drug activity: Pro-drugs
Inactive precursors, metabolised to active metabolites
E.g. cyclophosphamide, simvastatin, ramipril, perindopril
Reduced first pass metabolism = reduced bioavailability of pro-drugs
Sites of drug metabolism at cellular level:
Endoplasmic reticulum (microsomes):
The endoplasmic reticulum (especially smooth endoplasmic reticulum) of liver and other tissues contain a large variety of enzymes, together called microsomal enzymes
Enzymes occurring in organelles/sites other than endoplasmic reticulum (microsomes) are called non-microsomal enzymes.
Cytosol (soluble fraction): many water soluble enzymes
Mitochondria
Lysosomes
Nucleus
Factors affecting drug metabolism:
Species differences
Genetic differences: single nucleotide polymorphisms (SNPs)
Age: enzyme expression changes
Sex: under influence of sex hormones
Nutrition: food-drug interactions and malnutrition
Pathological conditions: i.e. liver disease
Drug excretion:
The kidney is the most important organ for the excretion of drugs and/or their metabolites
There are three important processes involved in renal excretion
Glomerular filtration
Tubular Secretion
Tubular reabsorption (reduces drug excretion)
Some compounds are also excreted via bile, sweat, saliva, exhaled air, or milk, the latter a possible source of unwanted exposure in nursing infants.
Clearance:
Clearance describes the rate of irreversible removal of a drug from plasma
Fundamental PK parameter for elimination
Involves both metabolism and excretion
This includes excretion of the unchanged drug as well as metabolism (biotransformation) as the parent compounds has been eliminated from the blood, even if the metabolite persists
Defined as ‘volume of plasma cleared of drug per unit time’
Total clearance:
Each organ of elimination has its own drug clearance value:
Hepatic (liver) clearance = CLh
Renal (kidney) Clearance = CLr
Clearance is additive, Total Clearance (Cltot):
CLtot = CLh+ CLr + CLother
Renal clearance:
The renal clearance of a drug is related to the kidney/renal function
Renal function
is related to age, sex, weight
can be compromised by the effects of some drugs
whilst some patients may have a condition that impairs their renal function
Dose adjustments
Doses for drugs with a high percentage cleared by the kidney can be adjusted according to the patients’ estimated renal function
Renal function can be estimated using a simple measurement of plasma creatinine
Drug elimination and half life
The half-life (t1/2) of a drug is effectively a measure of the speed with which it is eliminated from the body.
Time taken for plasma drug concentration to drop by half
It is a parameter of a first-order process – i.e. constant proportion of drug eliminated per unit time.
Graph on slide 16 of Pk1 lecture 2
What influences half-life?
Half life is determined by both clearance and volume of distribution such that:
T 1/2 = 0.693 x Vd/ CL
An INCREASE in Vd results in and INCREASE in t1/2
An INCREASE in CL results in a DECREASE in t1/2
A drug must be present in plasma to be available for clearance, hence large Vd (i.e. distributed to peripheral tissues) increases time taken to clear drug from body.
