Impact of Drugs
The liver is the principal site of drug metabolism . Although metabolism typically inactivates drugs, some drug metabolites are pharmacologically active—sometimes even more so than the parent compound. An inactive or weakly active substance that has an active metabolite is called a prodrug, especially if designed to deliver the active moiety more effectively.
Drugs can be metabolized by oxidation, reduction, hydrolysis, hydration, conjugation, condensation, or isomerization; whatever the process, the goal is to make the drug easier to excrete. The enzymes involved in metabolism are present in many tissues but generally are more concentrated in the liver. Drug metabolism rates vary among patients. Some patients metabolize a drug so rapidly that therapeutically effective blood and tissue concentrations are not reached; in others, metabolism may be so slow that usual doses have toxic effects. Individual drug metabolism rates are influenced by genetic factors, coexisting disorders (particularly chronic liver disorders and advanced heart failure), and drug interactions (especially those involving induction or inhibition of metabolism).
For many drugs, metabolism occurs in 2 phases. Phase I reactions involve formation of a new or modified functional group or cleavage (oxidation, reduction, hydrolysis); these reactions are nonsynthetic. Phase II reactions involve conjugation with an endogenous substance (eg, glucuronic acid, sulfate, glycine); these reactions are synthetic. Metabolites formed in synthetic reactions are more polar and thus more readily excreted by the kidneys (in urine) and the liver (in bile) than those formed in nonsynthetic reactions. Some drugs undergo only phase I or phase II reactions; thus, phase numbers reflect functional rather than sequential classification.
Hepatic drug transporters are present throughout parenchymal liver cells and affect a drug’s liver disposition, metabolism, and elimination. The 2 primary types of transporters are influx, which translocate molecules into the liver, and efflux, which mediate excretion of drugs into the blood or bile. Genetic polymorphisms can variably affect the expression and function of hepatic drug transporters to potentially alter a patient's susceptibility to drug adverse effects and drug-induced liver injury. For example, carriers of certain transporter genotypes exhibit increased blood levels of statins and are more susceptible to statin-induced myopathy when statins are used for the treatment of hypercholesterolemia.
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Pharmaceutical Analytical Chemistry