Abstract
Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues. Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In future, it may help to identify individuals at greatest risk of drug interactions and adverse events.
Highlights
The cytochrome P450 (P450 or CYP) isoenzymes are a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes, it takes part in the metabolism of many drugs, steroids and carcinogens [1]
The most intensively studied route of drug metabolism is the P450-catalysed mixedfunction oxidation reaction which conforms to the following stoichiometry
The activities of the CYP2C19 [4,5,6,7] and CYP2D6 [8,9,10,11,12,13,14] enzymes are biomedically distributed in the population, allowing classification of individuals as either extensive (EM) or poor metabolizers (PM)
Summary
The cytochrome P450 (P450 or CYP) isoenzymes are a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes, it takes part in the metabolism of many drugs, steroids and carcinogens [1]. A P450 species that catalyzes the metabolism of terfenadine was identified recently as CYP3A [88,89] during investigations of the mechanism of interactions with macrolides Another type is non-competitive inhibition, where the inhibitor binds at a site on the enzyme distinct from the substrate, as happens in classical studies of enzymology. Such examples include interactions between cimetidine and a number of drugs. Grapefruit juice increased the effects of triazolam, drowsiness being significantly (P < 0.05) enhanced As it has been described in a paper [127] that other flavonoids (quercetin for example) may be major inhibitors of metabolism, the results of future studies are awaited with interest. As for dihydropyridine calcium channel blockers, it is quite possible that interactions with rifampicin may develop, since most of these drugs are metabolized by CYP3A4 [143,144,145,146,147,148,149,150,129]
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