Pharmacokinetics
Objectives:
- Know and understand the routes of drug metabolism
- Phase I - Addition os a functional group
- Phase II Conjugation
- how metabolism can change drug action and toxicity
- pro drugs
- metabolic shunts
- adverse drug interactions
Content:
What is drug metabolism
Organism in consumption, are exposed to harmful substances and have the need to clear these substances from themselves
the same pathways determine pharmcokinetics in the body
There is variation in metabolism as people are diiferent
Pharmacokinetic models
you need to be able to account for all the places the drug goes and all the metabolites that come from the
Pharmacokinetic modeling
Drug metabolism affects excretion pharmacokinetics for hydrophobic drugs
drug metabolites are often more water soluble than the drug themselves metabolites can have different activity and toxicity when compared to original drug
Stages of drug metabolism
Phase I
the drug is oxidised or reduced or hydrolysed as a result the metabolite contains a functional group
Phase II
the drug is conjugated (linked) to another molecule to make it more water soluble and improve its recognition by drug transporters
Phase I enzymes
| Major phase 1 enzymes | Action |
|---|---|
| Cytochrome P450s (CYPs) MAJOR | C, O oxidation |
| Flavin Containing Monooxygenases (FMO) | N,S,P oxidation |
| Alcohol dehydrogenases | Alcohol Reduction |
| Aldehyde dehydrogenases | Aldehyde reduction |
| NADPH-Quinone oxidoreductases | Quinone reduction |
| Esterases | Hydrolyse esters |
| Epoxide hydrolases | Hydrolyse epoxides |
Cytochrome P450 family is by far the major phase I enzyme. This is denoted by CYP It adds hydroxide groups to molecules. this makes a drug more hydrophilic
nomenclature CYP2d6*1 encodes form normal protein varient of CYP2d6
CYP2d6*17 denote a varient protein
depending how the same drug collides with the enzyme different products can be made
CYP3A is the major drug metaboliser found in intestinal epithelium and liver 50% of CYP activity wide selection
Phase II Enzymes
| Major phase II Enzymes | Action |
|---|---|
| Sulfotransferases (SULT) | Adds sulfate |
| UDP-glucuronosyltransferases (UGT) | Adds glucuronic acid |
| Glutathione-S-transferases (GST) | Adds glutathione |
| N-acetyl transferases (NAT) | Adds the acetyl group |
| Methyltransferase (MT) | Adds the methyl group |
| The share of Phase II enzymes are far more diverse compared to phase I |
UGTs add glucuronic acid to electrophiles to form glycosides SULTs adds a sulfate group to oh and nh GSTs adds GSH to electrophilic molecules GSH is also an antioxidant. depletion can lead to oxidative damage
Metabolism can alter drug activity and toxicity
Prodrugs prodrugs are drugs designed so that the metabolite is the theraputically active agent
metabolic shunts cellular levels of conjugates can be exhausted and the drug is processed through secondary pathways. this creates different metabolites compared to the primary pathway
Induction of CYP3A activity
some drugs reliably result in increased metabolic proteins and higher processing. this mechanism is slow but the final result is heightened metabolic processing,
mechanism of CYP3a activity there is a receptor which recognises unknown molecules and triggers CYP3a production as a safeguard