Pharmacokinetics Flashcards
What are the solute carrier transporters?
OAT and OCT, non-selective, facilitative and secondary active transporters
What are ABC transporters?
ATP binding cassettes, e.g. P glycoproteins
What are P-glycoproteins?
P glycoprotein (P-gp) is an active transporter that protects the body from some harmful substances by transporting the substance out of the body or out of sensitive organs
What happens when the P-glycoprotein is inhibited?
Drugs enter GIT cells to be absorbed, diffuse into the brain, less elimination via kidneys
What happens when the P-glycoprotein is active?
Gut cells transport drugs into lumen
drugs leave brain
drugs enter kidney tubules
Equation for volume of distribution
Vd = Ab/ Cp
Ab= dose, Cp= plasma concentration
What are the 3 aspects of renal drug elimination?
- Glomerular filtration (urine)
- Tubular secretion (urine)
- Reabsorption (into plasma)
What are phase 1 reactions?
Catabolic, functionalisation, oxidation, reduction, hydrolysis
Increase polarity and make drug more water soluble
What are phase 2 reactions?
Anabolic, conjugation, combining with endogenous molecule (e.g. methyl, acetyl, glucuronyl) to make more water soluble
Explain phase II drug metabolism
- occurs mainly in the liver
- metabolite is pharmacologically inactive, less lipid soluble, excreted into urine or into bile/ faeces
- enzymes are potentially saturable (OD consequences)
- not considered important for drug-drug interactions
Explain phase I drug metabolism
Occurs in liver and other tissues (e.g. intestine)
- GI wall –> portal vein –> liver –> metabolising enzymes
- metabolites may be more active/ toxic (e.g. paracetemol –> toxic metabolite is inactivated by conjugation enzymes which can be used up in OD)
- Potential site for drug-drug interactions
Phase 1 drug metabolising enzymes
- broad substrate specificity
- 1 enzyme may catalyse the metabolism of many diff drugs
- 1 drug may be metabolised by multiple enzymes/ isoenzymes
What are Cytochrome p450s?
Liver drug metabolising enzymes usually microsomal- embedded in ER
- catalyse oxidative metabolism of a range of xenobiotics and endogenous substances
- 70% of drugs are metabolised by these
- main: CYP1, CYP2, CYP3
How do Cytochrome p450s vary?
- amino acid sequence
- sensitivity to inhibitors and inducing agents
- substrate specificity
What does the CYP450 reaction require?
O2, NADPH, NADPH-P450 reductase
Caution when elimination involves enzymatic metabolism
metabolising enzymes
o are potentially saturable (therapeutic dose is close to saturable level)
o activity can be influenced by many factors
♣ genetics (variance in metabolism)
♣ other drugs (can inhibit/ induce)
CYP450 inhibition
drug interactions via metabolising enzymes
- enzyme inhibition
o drugs metabolised by the same enzyme, if administered together will compete for the metabolising enzyme
CYP450 induction
- enzyme induction
o some drugs can increase activity/ levels of the enzymes that metabolise them (e.g. alcohol, barbiturates), tolerance increases (higher dose must be taken to have a higher effect)
CYP450 other interactions
- interaction between drugs and “herbal” medicines (St Johns Wort- antidepressant, effective with less side effects but is good at inducing cytochrome p450 enzymes interferes with metabolism of other drugs) or food components (e.g. grapefruit juice inhibits cyp450 enzymes)
inhibition of cyp2D6 reduced analgesic effect
other routes for excretion of drugs
- lungs: can remove gases and volatile liquids (e.g. many general anaesthetics), alcohol (concentration in lungs is similar to concentration in plasma)
- sweat, saliva, mucous, tears & milk: can excrete small amounts of drugs (some in milk can be dangerous to infants)
- Gut: some drugs can be excreted via bile faeces
o Potential for enterohepatic cycling
Enterohepatic cycling
Conjugated metabolites can be de-conjugated in gut and reabsorbed but bacteria to extend drug stay in body
Constant infusion
Administration curve is mirror image of elimination curve
- Constant by constant infusion (plasma concentration increases then steadies)
o Steadied off due to elimination occurring
o Drug stopped: falls down (elimination)
o <10 % remaining = effectively cleared from the body
Repeated dosing
More practical
-o fluctuations in plasma concentrations
o aim: to keep plasma conc at/ above steady state level
How can we quantify drug elimination?
Clearance = volume of plasma cleared of drug per unit time
Cl total = CL renal + Cl liver + Cl other
Clearance is dependent on:
- Liver: hepatic blood flow, intrinsic clearance, concentration of drug in plasma
- Renal: conc of drug in urine, urine flow rate, conc of drug in plasma
plasma half life
Time to eliminate drug is about 4-5 half lives
Time to reach steady state is 4-5 half lives (dosing frequency)
First order drug elimination kinetics
Elimination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration
Zero order drug elimination kinetics
The plasma concentration – time profile during the elimination phase is linear. For example 1.2 mg are eliminated every hour, independently of the drug concentration in the body. Order 0 elimination is rather rare, mostly occurring when the elimination system is saturated.
No defined half life
Rate of elimination, maintenance dose rate and the loading dose
RE = CL * [Plasma] DR = CL * target [] LD = Vd * target [plasma]
Phase 2 enzymes examples
- glutathione transferase
- N-acetyl transferase
Pharmacogenetics of warfarin
- Metabolism occurs through CYP2C9
- Clinically relevant SNPs have been identified in CYP2C9
o Result in reduced enzymatic activity
o Decrease in metabolism - Even after adjusting the dose for variability in CYP2C9 status, there is still an amount of dosing variability in patients with similar alleles
- Additional variability: polymorphisms in the warfarin target vitamin K reductase complex (VKORC1)
polymorphisms in drug targets (pharmacodynamics)
- Receptors/ transporters/ ion channels/ growth factors are increasingly recognised as causing variation in drug response
- Polymorphisms can have direct effects on drug target genes that affect drug response
polymorphisms in the β2 adrenoceptor
- Short acting β2-adrenoceptor stimulants (salbutamol) are used in the treatment of asthma (relaxing airways smooth muscle)
- Regular use of salbutamol had detrimental effects in the long term treatment of asthma
o
1/6 of asthmatic patients have an arg/arg phenotype (codon 16) in the adrenoreceptor.
o This phenotype is associated with a strong response to an acute dose of salbutamol compared to the gly/gly phenotype
BUT
o With long term treatment, patients with arg/arg phenotype rapidly desensitise to beta agonist drugs, resulting in a decline in responsiveness
o Patients with the arg/arg phenotype should avoid long term use of beta 2 agonist bronchodilators.
