Lecture DetailsEdit

Elizabeth Davis; Week 2 MED1022; Pharmacology

Lecture ContentEdit

Drug metabolising enzymes are usually found intracellularly (eg smooth ER), drugs must cross the plasma membrane and are more likely found for lipophilic drugs as they are less likely to be excreted unchanged in the urine. Metabolism of drugs mainly occurs in the liver, makes lipid soluble drugs more water soluble so they can be excreted by the kidneys. After oral absorption, first pass through the liver may reduce the amount of drug that gets into the general circulation (first pass). Phase 1 reactions are catabolic (functionalisation) such as oxidation, reduction or hydrolysis. They increase polarity and make drugs more water soluble. Phase 2 reactions are synthetic (conjugation) reactions, the drug/metabolite is combined with an endogenous molecule to make it more water soluble. Not all products of Phase 1 are non-toxic and inactive, some are only active when metabolised (zymogens). One enzyme may catalyse metabolism of many different drugs. One enzyme isoform may be involved in metabolism of the same drug. There are usually multiple forms of individual drugs, interindividual differences in drug metabolism. Isoforms/isoenzymes catalyse the same reaction, have different amino acid sequences, kinetic parameters, substrate specificity and regulation.

CYP450 is superfamily of related enzymes involved in phase I reactions, they catalyse the oxidative metabolism of many xenobiotics and differ in sensitivity to inhibitors, inducing agents and in specificity of reactions catalysed. The P number indicates the gene family, the next letter the subfamily, and the number the individual gene. P1A2 is caffeine, theophylline, paracetamol; P2C9 is ibuprofen, warfarin, P2D6 is ethanol, paracetamol. Phase I reactions that do not involve P450 include alcohol dehydrogenase metabolism, MAO inactivating active amines, hydrolytic reactions that occur in plasma (aspirin > salicylic acid). Other sites of drug metabolism include plasma, lung and gut. Enzyme induction can increase activity of enzymes that metabolise them. Drugs may compete for the same enzyme causing enzyme inhibition.

Phase II reactions usually create a metabolite that is pharmacologically inactive, less lipid soluble and excreted in urine or bile. First order elimination is where rate of elimination is proportional to plasma concentration. Zero order is where rate of elimination is constant and independent of plasma concentration. Zero order drugs are alcohol (at all but extremely low doses), aspirin (moderate to high doses) and phenytoin (moderate to high doses).

Drugs with first order kinetics can have t1/2 determined as a constant fraction is eliminated per unit time. Drugs with zero order kinetics will have t1/2 vary depending on dose. Repeat dosing of first order kinetics will reach a steady state concentration but concentrations will fluctuate with dosing (smaller and more frequent dosing closely resembles IV infusion. Time to steady state is 4-5t1/2s.

Factors affecting dose are age (children metabolise quicker than adults, conjugation occurs more slowly), elderly patients start low. Disease can also affect dose e.g. liver or kidney disease. Intestinal disease has change in CYP activity in celiac disease. Viral infections may suppress hepatic CPY.