ICPP 17 - Pharmacokinetics 2 Flashcards
Define “elimination” in the context of pharmacokinetics.
Elimination covers both excretory and metabolic processes, and removes both exogenous and endogenous species, which is a protective and homeostatic function.
What is the role of phase l and phase ll metabolic enzymes?
Where is there a large reserve of these enzymes?
- To increase the ionic charge of drugs and thus enhance renal elimination (lipophilic drugs are able to diffuse out of the renal tubules back into plasma)
- Once metabolised, drugs are usually inactivated (however this is NOT ALWAYS the case)
- Large hepatic reserve of phase l & ll enzyme - however some present in the gut too.
Which enzymes carry out phase l metabolism?
What reactions do they undertake?
Where are they found?
- CYP450 enzymes - a large group of 50 + isoenzymes
- Versatile generalists that metabolise a wide range of molecules and catalyse redox, dealkylation & hydroxylation reactions to increase ionic charge
- On the external face of the SER.
Give an example of a pro-drug that is activated by phase l metabolism rather than deactivated.
Codeine is metabolised to form morphine (roughly 15% metabolised by CYP2D6 to morphine) which has 200x affinity for Opioid U-receptor compared to codeine.
Which enzymes carry out phase ll metabolism reactions?
What reactions do they catalyse and why?
- Phase ll enzymes are cytosolic enzymes
- They catalyse conjugation reactions - e.g.: sulphation, glucorinadation, glutathione etc - to once again increase ionic charge for enhanced renal elimination.
Which one of the main 6 CYP450 enzymes that catalyse roughly 90% of all drug metabolisms, is responsible for 36% of all drugs?
- CYP3A4/5
What are the main factors that may affect drug metabolism?
- Age (reduced in elderly)
- Sex (e.g.: slower alcohol metabolism in women)
- General health/disease
- CYP450 induction or inhibition by other drugs
How can some other drugs induce CYP450 enzymes?
What does this mean for the rate of elimination and plasma levels of other drugs given?
- Increased transcription + translation, and slower degradation of CYP450 enzymes
- Increased rate of elimination, therefore decreased levels of drug in plasma
- This has serious therapeutic consequences - induction process typically over 1-2 weeks.
How can some other drugs inhibit CYP450 enzymes?
What does this mean for the rate of elimination and plasma levels of other drugs given?
- Via competitive/non-competitive inhibition
- Inhibition of CYP450 enzymes = decreased rate of elimination and increased plasma levels of concurrent drugs.
- Significant therapeutic effects - inhibition = 1 to a few days.
How can genetic variation of CYP450 enzymes affect phase l metabolism?
CYP2C19 not expressed in 5% caucasians and 30% asians - which metabolises valium + phenytoin - therefore need to consider safety/efficacy in these non-metabolisers.
What is the main route of drug elimination?
What are the 3 processes of this route?
What are some potential other routes of drug elimination?
- The kidney via urine
- Glomerular filtration, active tubular secretion, passive tubular reabsorption
- Sweat, bile, saliva, breast milk & tears
How does drug excretion occur in glomerular filtration and proximal tubular secretion?
- Glomerulus receives 20% of renal blood flow - unbound drug enters the Bowman’s capsule
- Remaining 80% goes to peritubular capillaries - high expression of OCT’s and OAT’s here. They carry ionised molecules out (reverse process of the small intestine)
What type of drugs can be reabsorbed into the blood in the distal tubule?
Lipophilic drugs - carrying no charge.
How does the pH of the urine affect absorption of weak acids and bases?
Weak acids:
- Acidic urine increases absorption - as acid cannot lose its proton to a base (therefore is neutral)
- Alkaline urine decreases absorption - as acid gets rid of its proton to become charged
Vice versa for weak bases.
What is drug clearance and how is it calculated?
- Drug clearance is the rate of elimination of a drug from the body from all routes
- For most drugs:
Total body clearance = hepatic clearance + renal clearance. - Measured via Vd (volume of distribution) measured in ml/min.
