Drug metabolism UF - Lecture notes PDF

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BI514 Pharmacology Dan Lloyd Drug metabolism and distribution ADME: Absorption, distribution, metabolism and elimination

Metabolism of drugs is divided into 2 distinct phases The purpose of drug metabolism is to eliminate it from the body, usually via aqueous routes (the urine in particular) Drugs are metabolised by enzymes that have evolved to detoxify potentially harmful molecules The collective purpose of these enzymes is to render these rather hydrophobic molecules more water-soluble to facilitate excretion

Phase I metabolism by cytochrome P450 enzymes Phase 1 metabolism is a catabolic reaction and takes place in the liver Cytochrome P450 family are examples of enzymes involved in Phase 1 metabolism Each member of this family has distinct substrate specificiy, although there is also significant overlap and a degree of redundancy At least 70 proteins have been identified, subdivided into CYP1, CYP2 and CYP3 subgroups An iron-containing heme centre catalyses hydroxylation at a carbon-hydrogen bond – ordinarily a very difficult chemical reaction due to the thermodynamic stability of a C-H bond Mechanism of action relates to redox activity of iron ion the centre of heme and its changes between electronic configurations Starts with Fe3+ at the core of heme; iron is in low-spin state Addition of drug molecule (‘DH’) containing a carbon-hydrogen bond elicits conformational change and facilitates reduction of Fe 3+ by switching the ion to the high spin state

The complex receives an electron from NADPH–P450 reductase (acting as an electron donor), which reduces the iron to Fe2+ and the electronic configuration changes to the high spin state The complex combines with molecular oxygen, followed by a proton and a second electron (either from NADPH–P450 reductase or from cytochrome b5) to form a peroxide complex (Fe2+OOH–DH) This combines with another proton, cleaving the peroxide complex to generate water and a ferric oxene (FeO)3+–DH complex, and the iron ion returns to its low spin state. (FeO)3+ is a powerful complex able to remove a hydrogen atom from DH, with the formation of a pair of short-lived free radicals (D . And Fe2+OH.) which combine to generate oxidised drug (‘DOH’), and regenerated of P450 enzyme Phase 2 metabolism by conjugation to hydrophilic molecules A common example is conjugation of the phase 1 metabolite to a glucuronide via a glycosidic bond This process is catalysed by UDP-glucuronyl transferase

Some enzymes involved in Phase I metabolism are inducible...