Metabolic Stability – Hepatocytes

Background

Drugs are most often eliminated by biotransformation and/or excretion into urine or bile. The liver

is the major organ for xenobiotic biotransformation

and is thereby important in characterizing the

metabolism, toxicology, and drug-drug interaction

properties of drugs. Drug metabolism is achieved

via two major enzyme reactions within the liver,

Phase I and Phase II reactions. Phase I enzymes

include the cytochrome P450 (CYP) family of

enzymes which are located in the smooth

endoplasmic reticulum. The basic processes in

phase I reactions are oxidation, reduction and/or

hydrolysis many of which are catalyzed by the

CYP system and require NADPH as a cofactor.

Phase II enzymes are located in the cytoplasm and

endoplasmic reticulum and are characteristic of

conjugation reactions including glucuronic acid,

glutathione, sulfate, and glutamine conjugations.

Phase II reactions generally inactivate the drug if

it is not already therapeutically inactive following

Phase I metabolism, and make the drug more water

soluble to facilitate its elimination. Some drugs are

metabolized by Phase I or Phase II enzymes alone

whereas others are metabolized by both Phase I

and Phase II enzymes.