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Second level
Third level
Fourth level
Fifth level
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Second level
Third level
Fourth level
Fifth level
Principles of Pharmacology and Toxicology (BIOL3020)
Drug Elimination
e
Drug Metabolism
This involves the enzymatic conversion of one chemical entity (drug) to another (metabolite)
Metabolism converts drugs into more polar chemicals
This conversion may lead to a pharmacologically active metabolite
Or may lead to a toxin being formed
Drug
Polar
Chemical
(Active metabolite or Toxin)
Elimination
Drug Metabolism
The P450 Pathway
.
/
Drug Metabolism
The OH serves as the point of attack for phase II system to attach a substituent such as glucuronide by another enzyme
UDP-glucuronyl transferase
This forms an inactive, readily excretable product
Both phases increase water solubility
The P450 Family of Enzymes
There are three main cytochrome P450 enzymes (CYP1, CYP2 and CYP3)
There are different subclasses within each
Different drugs are substrates for different P450 enzymes
Isoenzyme P450
Drug
CYP1A1
Theophylline
CYP1A2
Caffeine, paracetamol, tacrine, theophylline
CYP2A6
Methoxyflurane
CYP2C8
Taxol
CYP2C9
Ibuprofen , phenytoin , tolbutamide , warfarin
CYP2C19
Omeprazole
CYP2D6
Clozapine , codeine, debrisoquine, metoprolol
CYP2E1
Alcohol, enflurane , halothane
CYP3A4/5
Ciclosporin, losartan, nifedipine , terfenadine
From Pichard et al. (1995) Predictability of drug metabolism from in vitro studies. In Alvan G et al. (eds) COST B1 conference on variability and specificity in drug metabolism. European Commission, Luxembourg, pp. 45-56.
Variations in P450 Activity
Environmental Influence
Enzyme inhibitors and inducers are present in the diet and environment
Grapefruit juice inhibits drug metabolism
Brussels sprouts and cigarette smoke induce P450 enzymes.
Metabolism can alter drug properties
Aspirin inhibits some platelet functions and has anti-inflammatory activity
It is hydrolysed to salicylic acid, which has anti-inflammatory but not antiplatelet activity
Metabolism can convert inactive prodrugs into active drugs or toxins
See table 8.3 in text and www.studentconsult.com.
Some drug metabolites are the active form
Some metabolites are toxins
Some metabolites have the same activity as the original drug
Drug and Metabolite Elimination
Renal excretion is the most common form of elimination
About 20 of drug, cross the glomerular filter of the kidney.
80 is transported from the peritubular capillaries to the tubules by active transport
Especially weak acids and bases
Active Transport
Tubule
Glomerular
filter
Drug and Metabolite Elimination
Lipid-soluble drugs are passively reabsorbed by diffusion across the tubule back to the blood
are not efficiently excreted in the urine.
Because of pH partition, weak acids are more rapidly excreted in alkaline urine, and vice versa.
Active Transport
Tubule
Urine pH affects Elimination and Drug Response
Alkaline urine will cause acidic drugs to be eliminated faster
Urine pH affects drug response and plasma concentration
Pharmacokinetic Plots
Toxicokinetics
v
Stine and Brown (2006) Principles of Toxicology
Toxicokinetics
p
Stine and Brown (2006) Principles of Toxicology
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