G2. Drug metabolism and excretion Flashcards
Describe drug metabolism
-Predominantly occurs in the liver
-Hepatocytes express a range of broad-spectrum metabolic enzymes
-Hepatic portal system leads to first-pass metabolism
what are the two 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?
-increase molecule size and hydrophilicity
-Decreases passive diffusion across cell membranes
-Decreases binding affinity for target molecules
-Promotes excretion
Describe phase 1: cytochrome P450
-Cytochrome P450 (CYP450) is a family of enzymes found in cells, primarily in the liver, that play a critical role in the metabolism of drugs, toxins, and other substances in the body.
-Haem-containing mono-oxygenase enzymes that can catalyse many reactions on many substrates
-Multiple isoforms expressed (74 gene families)
-Catalytic mechanism involves cyclic reduction and oxidation of haem iron centre
what is an isoform?
An isoform is a variant of a protein that arises from the same gene but differs slightly in its structure or function.
Describe Cytochrome P450 isoforms
-Wide range of substrates and reactions
-Diversity of P450 isoforms covers most substrates
-Broadly protective mechanism for eliminating “xenobiotics”
Describe induction and inhibition of metabolic enzymes
major mechanism for drug interactions
Describe induction of metabolic enzymes
-Genes coding for metabolic enzymes can be induced
-Upregulation of gene expression increases levels of enzyme
-Increases metabolism of all common substrates
e.g. Phenytoin induces CYP3A subfamily
Describe inhibition of metabolic enzymes
-Some drugs can inhibit metabolic enzymes
-Decreases metabolism of all common substrates
e.g. Erythromycin inhibits CYP3A subfamily
Inhibition of CYP3A4 by grapefruit juice?
ONE NOTE
Describe phase 2; conjugation
-Addition of polar/charged groups to reactive centres:
OH (glucuronyl, methyl, sulphate)
NH2 (glucuronyl, acetyl)
COOH (glucuronyl, glycine)
-Commonest conjugation is catalysed by UDP-glucuronyl transferases (dozens of gene families)
-Makes drugs less reactive, and more readily excreted by kidneys
ONE NOTE
Describe the active metabolites consequences of metabolism
-Active metabolites
-Products of drug metabolism may still be active
-Active metabolites may have differing pharmacokinetics to parent compound
Describe the pro-drugs consequences of metabolism
-Administered parent drug may be biologically inactive
-Depends on metabolism to form active species
Describe the side effects consequences of metabolism
Metabolite may have enhanced toxicity compared to parent drug
Describe the metabolism of diazepam
-Multiple routes
-Multiple intermediates
-Metabolites are active, but have differing properties and half lives
ONE NOTE
Describe excretion
Multiple routes:
-Kidney (water soluble)
-Lung (volatiles)
-Bile (large molecular weights)
Describe biliary excretion
-Large molecules can be actively transported into bile
-Excreted into gut (enterohepatic re-circulation)
-(Re)absorption can be blocked by active elimination (e.g. activated charcoal)
ONE NOTE
Describe renal excretion
-Role of kidney tubule is to clear blood of waste products while retaining essential ions and nutrients
-Also crucial to electrolyte and water homeostasis
what are the three stages for drug clearance in renal excretion?
-Glomerular filtration
-Tubular secretion
-Reabsorption
Describe glomerular filteration in renal excretion
-Hydrostatic and osmotic pressure promotes fluid movement from fenestrated capillaries into Bowman’s capsule.
-Small molecules (including drugs) carried by bulk flow, but plasma proteins are excluded
-Free concentration of drug carried over passively
ONE NOTE
Describe active secretion in renal excretion
-Transporter proteins carry small molecules across apical cells into tubule lumen in proximal tubule
-Driven by energy (co-transport of ions or ATP hydrolysis), therefore active transport
-Concentration of drug can occur
ONE NOTE
What are the two major transporter classes in renal excretion?
-Organic cation transporters (OCT)
-Organic anion transporters (OAT)
Describe organic cation transporters (OCT)
-Transports a broad range of monovalent cations
-Uses membrane potential as driving force
-Basic drugs secreted
Describe organic anion transporters (OAT)
-Transports a broad range of monovalent anions
-Anion exchange with dicarboxylic acids
-Acid drugs secreted
Describe reabsorption in renal excretion
-Both passive and active reabsorption occurs
-For drugs and metabolites, mostly passive reabsorption in distal tubule
-Lipophilic drugs reabsorbed, hydrophilic drugs/metabolites retained
ONE NOTE
What is 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
Describe time course for elimination from plasma
-Elimination will remove drug at a rate determined by free concentration (law of mass action)
-First order kinetics
-Exponential time course
ONE NOTE
How to measure elimination?
-Half life (t1/2)
-Clearance (CL)
Describe Half life (t1/2)
-Time taken for plasma levels to halve
-Good for estimating dosing intervals
ONE NOTE
Describe clearance (CL)
-Volume of plasma cleared of drug in a unit of time
-Commonest measure of elimination
Renal excretion and hepatic metabolism can be expressed as separate clearance volumes (CL):
CLp = CLr + CLh (i.e. total clearance is the sum of the two routes)
t1/2 =
0.693Vd/ CLp
ONE NOTE
How can clearance be compared to GFR?
-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
ONE NOTE
Describe variation across the lifespan; elimination
-Liver and kidney function are reduced in newborns and elderly
-Expression patterns of metabolic enzyme vary with age
-Variation in body composition will affect estimates of glomerular filtration rates
-Also relevant for variation due to sex, ethnicity and pre-existing disease
