Although every tissue has some ability to metabolize drugs, the liver is the principal organ of drug metabolism. Other tissues that display considerable activity include the gastrointestinal tract, the lungs, the skin, the kidneys, and the brain. After oral administration, many drugs (eg, isoproterenol, meperidine, pentazocine, morphine) are absorbed intact from the small intestine and transported first
FIGURE 4–1 Phase I and phase II reactions, and direct elimination, in drug biodisposition. Phase II reactions may also precede phase I reactions.
via the portal system to the liver, where they undergo exten-and fractionation of the cell, they re-form into vesicles called sive metabolism. This process is called the first-pass effect (see microsomes. Microsomes retain most of the morphologic and Chapter 3). Some orally administered drugs (eg, clonazepam, functional characteristics of the intact membranes, including chlorpromazine, cyclosporine) are more extensively metabolized the rough and smooth surface features of the rough (ribosomein the intestine than in the liver, while others (eg, midazolam) studded) and smooth (no ribosomes) endoplasmic reticulum. undergo significant (~50%) intestinal metabolism. Thus, intesti-Whereas the rough microsomes tend to be dedicated to protein nal metabolism can contribute to the overall first-pass effect, and synthesis, the smooth microsomes are relatively rich in enzymes individuals with compromised liver function may rely increasingly responsible for oxidative drug metabolism. In particular, they on such intestinal metabolism for drug elimination. Compromise contain the important class of enzymes known as the mixed funcof intestinal metabolism of certain drugs (eg, felodipine, cyclo-tion oxidases (MFOs), or monooxygenases. The activity of these sporine A) can also result in significant elevation of their plasma enzymes requires both a reducing agent (nicotinamide adenine levels and clinically relevant drug-drug interactions (DDIs, see dinucleotide phosphate [NADPH]) and molecular oxygen; in a below). First-pass effects may limit the bioavailability of orally typical reaction, one molecule of oxygen is consumed (reduced) administered drugs (eg, lidocaine) so greatly that alternative routes per substrate molecule, with one oxygen atom appearing in the of administration must be used to achieve therapeutically effective product and the other in the form of water. blood levels. Furthermore, the lower gut harbors intestinal micro-In this oxidation-reduction process, two microsomal enzymes organisms that are capable of many biotransformation reactions. play a key role. The first of these is a flavoprotein, NADPH-In addition, drugs may be metabolized by gastric acid (eg, peni-cytochrome P450 oxidoreductase (POR, or CPR). One mole cillin), by digestive enzymes (eg, polypeptides such as insulin), of this enzyme contains 1 mol each of flavin mononucleotide or by enzymes in the wall of the intestine (eg, sympathomimetic (FMN) and flavin adenine dinucleotide (FAD). The second catecholamines). microsomal enzyme is a hemoprotein called cytochrome P450,