G2 Metabolism and excretion Flashcards
where does drug metabolism mainly occur?
in the liver
- hepatocytes express a range of broad-spectrum metabolic enzymes
- hepatic portal system leads to first-pass metabolism
what are the 2 phases of drug metabolism?
phase 1
- reactive centres introduced to drug molecules
phase 2
- conjugation of polar / charged groups at reactive centres
what is the overall effect of drug metabolism?
to increase molecule size and hydrophilicity
- decreases passive diffusion across cell membranes
- decreases binding affinity for target molecules
- promotes excretion
describe phase 1 of drug metabolism generally
- cytochrome P450
- haem-containing monooxygenase enzymes that can catalyse many reactions on many substrates
- multiple isoforms expressed
- catalytic mechanism involves cyclic reduction and oxidation of haem ion centre
describe the cytochrome P450 isoforms
- wide range of substrates and reactions
- diversity of P450 isoforms covers most substrates
- broadly protective mechanism for eliminating ‘xenobiotics’
describe the induction and inhibition of metabolic enzymes in phase I of drug metabolism
- major mechanism for drug interactions
genes coding for metabolic enzymes can be induced
- up regulation of gene expression increases levels of enzyme
- increases metabolism of all common substrates
- eg. phenytoin induces CYP3A subfamily
some drugs can inhibit metabolic enzymes
- decreases metabolism of all common substrates
- eg. erythromycin inhibits CYP3A subfamily
describe the inhibition of CYP3A4 by grapefruit juice
- dramatic increase in plasma concentration of simvastatin after a single 40 mg oral dose in subjects drinking 200 ml of grapefruit for 3 days
- inhibition of CYP3A4 greatly reduces impact of first-pass metabolism
in phase II of drug metabolism, what happens?
addition of polar / charged groups to reactive centres
- OH (glucuronyl, methyl, sulphate)
- NH2 (glucuronyl, acetyl)
- COOH (glucuronyl, glycine)
what is the most common conjugation catalysed by in phase II of drug metabolism?
- UDP-glucuronyl transferases (dozens of gene families)
- makes drugs less reactive and more readily excreted by kidneys
consequences of drug metabolism
- active metabolites
- prodrugs
- side effects
describe the consequence of active metabolites of phase II drug metabolism
- products of drug metabolism may still be active
- active metabolites may have different pharmacokinetics to parent compound
describe the consequence of prodrugs of phase II drug metabolism
- administered parent drug may be biologically active
- depends on metabolism to form active species
describe the consequence of side effects of phase II drug metabolism
metabolite may have enhanced toxicity compared to parent drug
describe the metabolism of diazepam
- multiple routes
- multiple intermediates
- metabolites are active but have different properties and half lives
what are the multiple routes of excretion?
kidney (water-soluble)
lung (volatiles)
bile (large molecular weights)
describe biliary excretion
- large molecules can be actively transported into bile
- excreted into gut (enterohepatic recirculation)
- (re)absorption can be blocked by active elimination (eg. activated charcoal)
what is the role of the kidney tubule?
- to clear blood of waste products while retaining essential ions and nutrients
- also crucial to electrolyte and water homeostasis
what are the 3 stages of drug clearance?
- glomerular filtration
- tubular secretion
- reabsorption
describe the first stage of renal excretion: glomerular filtration
- hydrostatic and osmotic pressure promotes fluid movement from fenestrated capillaries into Bowman’s capsule
- small molecules (including drugs) carrier by bulk flow, but plasma proteins are excluded
- free concentration of drug carried over passively
describe the second stage of renal excretion: active secretion
- transporter proteins carry small molecules across apical cells into tubule lumen in proximal tubule
- driven by energy (co-transport of ions of ATP hydrolysis) therefore active transport
- concentration of drug can occur
what are the 2 major transporter classes in active secretion (2nd stage of renal excretion)
organic cation transporters (OCT)
- transports a broad range of monovalent cations
- uses membrane potential as driving force
- basic drugs secreted
organic anion transporters (OAT)
- transports a broad range of monovalent anions
- anion exchange with dicarboxylic acids
- acid drugs secreted
describe the third stage of renal excretion: reabsorption
- both passive and active reabsorption occurs
- for drugs and metabolites, mostly passive reabsorption in distal tubule
- lipophilic drugs reabsorbed, hydrophilic drugs / metabolites retained
what is the estimated glomerular filtration rate (eGFR)?
- estimates kidney filtration rate in a given patient
- good for identifying renal impairment and tailoring dosing regimens
- calculated from serum creatinine levels (a byproduct of muscle metabolism that is efficiently filtered but not reabsorbed in the kidney)
- different equations can be used
describe time course for elimination from plasma
- elimination will remove drug at a rate determined by free concentration (law of mass action)
- not all drugs follow first order kinetics but the one in the image does (exponential time course)
2 methods of measuring elimination, describe them both
half-life
- time taken for plasma levels to half
- good for estimating dosing intervals
clearance
- volume of plasma cleared of drug in a unit of time
- most common measure of elimination
describe a time course of elimination of drug in terms of half-life, comparing intravenous and intravenous with impaired renal function
- intravenous injection of drug at t=0
- no absorption due to intravenous
- impaired kidney or liver function causes an increase in half-life
what is clearance?
- plasma clearance is the apparent volume of plasma that is cleared of drug per unit of time (units of ml/min or L/h)
- renal excretion an hepatic metabolism can be expressed as separate clearance volumes (CL)
how can clearance be compared to GFR?
- healthy male adult GFR is around 7.5 L/h (125 ml/min)
- that means 7.5L of plasma is being filtered through the kidneys every hour, carrying drug with it
- if renal clearance > 7.5 L/h, drug must be actively secreted
- if renal clearance < 7.5 L/h, drug must be reabsorbed
- if renal clearance = 7.5 L/h, drug must either be filtered only or secreted and reabsorbed to the same extent
describe the variations in elimination throughout lifespans
- liver and kidney function are reduced in newborns and elderly
- expression patterns of metabolic enzyme vary with age
- variation in body composition will affect estimate of glomerular filtration rates
- also relevant for variation due to sex, ethnicity and pre-existing disease
