Drug Elimination Flashcards
Where does drug metabolism occur?
In the liver
- hepatocytes express range of broad-spectrum enzymes
- hepatic portal vein leads
How many phases of drug metabolism
2
Phase 1
Reactive centres introduced to drug molecules
- haem-containing mono-oxygenase enzymes that catalyse many reactions on many substrates
- multiple isoforms expressed (74 gene families)
- catalytic mechanism involves cyclic reduction + oxidation of haem iron centre
Phase 2
Conjugation of polar/charged groups at reactive centres
- addition of polar/charge groups to reactive centres
- commonest conjugation is catalysed by UDP-glucuronyl transferases
- make drugs less reactive + readily excreted by kidneys
3 stages of drug clearance
Glomerular Filtrate
Tubular secretion
Reabsorption
3 mechanisms of drug interaction
1) Competition for binding sites
2) Modulation of cytochrome P450
3) Competition for secretion/absorption in kidney tubule
What to use to measure Elimination
Half life (t1/2)
Clearance (Cl)
Estimated glomerular filtrate rate (eGFP)
Half life
Time taken for plasma level to halve
Good for estimating dosing regimens
Clearance
Volume of plasma cleared of drug in a unit of time
Commonest measure of elimination
Half life
Time taken for plasma level to halve (fall by 50%)
Good for estimating dosing regimens
What can cause Nephrotoxicity
Aminoglycoside antibiotics
- By killing tubular epithelial cells which impairs renal function
- impaired renal function means filtration + secretion are reduced + elimination is slowed
2 major transporters
Organic ANION transporter
Organic CATION transporter
Organic anion transporter
Transports a broad range of monavalent anions
Anion exchange with dicarboxylic acids
Acid drugs secreted
Organic cation transporter
Transports a broad range of monovalent cations
Uses membrane potential as driving force
Basic drugs secreted
Drugs + metabolites reabsorbed
Passive reabsorption in distal tubule
Grapefruit Juice cause
Inhibition of CYP384
increase plasma concentration of oral dose of 40mg Simvastatin after subjects drank 200ml of Grapefruit juice
It reduces impacts of first-pass metabolism
Antibiotic interaction of Erythromycin
Inhibits CYP3A subfamily
- reduces impact of first-pass metabolism like grapefruit juice
Antibiotic interaction of Metronidazole
Inhibits acetaldehyde dehydrogenase
- interact with alcohol and cause nausea, dizziness
Other consequences of metabolism
Active metabolites
Pro-drugs
Side effects
Routes of excretion
Kidney (water-soluble)
Lung (volatiles)
Bile (large molecular weights)
Routes of excretion
Kidney (water-soluble)
Lung (volatiles)
Bile (large molecular weights)
Biliary excretion
Large molecules can be actively transported into bile
Excreted into gut (enterohepatic re-circulation)
Role of kidney tubule
Clear blood of waste products while retaining essential ions + nutrients
- Electrolyte & water homeostasis maintained
Calculate clearance from plasma
CLp(plasma) = CLr(renal excretion) + CLh(hepatic metabolism)
Calculate half life
t1/2 = 0.693Vd / CLp
What drugs are reabsorbed?
Lipophilic drugs
What drugs are retained?
Hydrophilic drugs
Cytochrome P450
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
Antibiotic interaction of Rifampicin
Induces CYP3A subfamily
- reduce levels of other medications metabolised
Bowmans Capsule
Glomerular filtration
Proximal tubule
Active secretion
Distal Convoluted Tubule
Reabsorption
What drives active secretion
Energy via Active transport
Impaired renal function
Filtration + secretion are reduced + elimination is slowed
The more nephrotoxicity…
The higher the drug plasma concentration will be
- aminoglycosides + renally-cleared drug at risk of over-dosing
What increase half life?
Impaired kidney / liver function
Consequences of metabolism
Active metabolites - products of drug metabolism is active - active metabolites may have differing pharmacokinetics to parent compound Prodrugs - parent drug may be inactive - depends on metabolism to form species Side effects - metabolite have enhanced toxicity compared to parent drug
How can reabsorption be blocked
By active elimination e.g. absorbents like charcoal retain in gut
Glomerular filtration
Hydrostatic + osmotic pressure promotes fluid movement from capillaries to bowman’s capsule
- small molecules carried by bulk flow but not plasma proteins
- free conc of drug carried over
Active secretion
Transporter proteins carry small molecules across apical cells into tubule lumen in proximal tubule
- Driven by energy (co-transport of ions/ATP hydrolysis)
- conc of drug can occur
Reabsorption
Both passive + active reabsorption occurs
- drugs + metabolites go through passive reabsorption in distal tubule
- lipophilic drugs reabsorbed, hydrophilic drugs retained
Probenecid
Competes with other drugs for organic anion transporters in proximal tubule
- to prolong action of penicillin antibiotics
- interacts with other drugs
Estimated glomerular filtration rate
Estimates kidney filtration rate in patient
- good in identifying renal impairment + tailoring dosing regimens
- calculated from serum creatinine levels - byproduct of muscle metabolism that is efficiently filtered but not reabsorbed in kidney
Calculate clearance
CLHepatic + CLRenal = CLPlasma
Calculate volume of distribution
t1/2=0.693Vd/ CLP
