Humans are exposed daily to a wide variety of foreign compounds called xenobiotics —substances absorbed across the lungs or skin or, more commonly, ingested either unintentionally as compounds present in food and drink or deliberately as Drugs for therapeutic or “recreational” purposes. Exposure to environmental xenobiotics may be inadvertent and accidental or—when they are present as components of air, water, and food—inescapable.
Some xenobiotics are innocuous, but many can provoke biologic responses. Such biologic responses often depend on conversion of the absorbed substance into an active metabolite. The discussion that follows is applicable to xenobiotics in general (including drugs) and to some extent to endogenous compounds.
Why drug biotransformation is important?
Renal excretion plays a pivotal role in terminating the biologic activity of some drugs, particularly those that have small molecular volumes or possess polar characteristics, such as functional groups that are fully ionized at physiologic pH. However, many drugs do not possess such physicochemical properties.
Pharmacologically active organic molecules tend to be lipophilic and remain unionized or only partially ionized at physiologic pH; these are readily reabsorbed from the glomerular filtrate in the nephron. Certain lipophilic compounds are often strongly bound to plasma proteins and may not be readily filtered at the glomerulus. Consequently, most drugs would have a prolonged duration of action if termination of their action depended solely on renal excretion.
An alternative process that can lead to the termination or alteration of biologic activity is Metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds.
Metabolic products are often less pharmacodynamically active than the parent drug and may even be inactive. However, some biotransformation products have enhanced activity or toxic properties. It is noteworthy that the synthesis of endogenous substrates such as steroid hormones, cholesterol, active vitamin D congeners, and bile acids involves many pathways catalyzed by enzymes associated with the metabolism of xenobiotics. Finally, drug-metabolizing enzymes have been exploited in the design of pharmacologically inactive prodrugs that are converted to active molecules in the body.
The role of biotransformation on drug disposition
Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of two major categories called phase I and phase II reactions.
Phase I reactions usually convert the parent drug to a more polar metabolite by introducing or unmasking a functional group (−OH, −NH 2, −SH). Often these metabolites are inactive, although in some instances activity is only modified or even enhanced.
If phase I metabolites are sufficiently polar, they may be readily excreted. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid combines with the newly incorporated functional group to form a highly polar conjugate. Such conjugation or synthetic reactions are the hallmarks of phase II metabolism.
A great variety of drugs undergo these sequential biotransformation reactions, although in some instances the parent drug may already possess a functional group that may form a conjugate directly. For example, the hydrazide moiety of isoniazid is known to form an N -acetyl conjugate in a phase II reaction. This conjugate is then a substrate for a phase I type reaction, namely, hydrolysis to isonicotinic acid. Thus, phase II reactions may actually precede phase I reactions.
Site for drug biotransformation
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 (e.g., isoproterenol, meperidine, pentazocine, morphine) are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism. This process is called the first-pass effect
Some orally administered drugs (e.g., clonazepam, chlorpromazine, and cyclosporine) are more extensively metabolized in the intestine than in the liver, while others (e.g., midazolam) undergo significant (≈ 50%) intestinal metabolism. Thus, intestinal metabolism can contribute to the overall first-pass effect, and individuals with compromised liver function may rely increasingly on such intestinal metabolism for drug elimination. Compromise of intestinal metabolism of certain drugs (e.g., felodipine, cyclosporine A) can also result in significant elevation of their plasma levels and clinically relevant drug-drug interactions
First-pass effects may so greatly limit the bioavailability of orally administered drugs (e.g., lidocaine) that alternative routes of administration must be used to achieve therapeutically effective blood levels. Furthermore, the lower gut harbors intestinal microorganisms that are capable of many biotransformation reactions.
In addition, drugs may be metabolized by gastric acid (e.g., penicillin), by digestive enzymes (e.g., polypeptides such as insulin), or by enzymes in the wall of the intestine (e.g., sympathomimetic catecholamines).
Although drug biotransformation in vivo can occur by spontaneous, noncatalyzed chemical reactions, most transformations are catalyzed by specific cellular enzymes. At the subcellular level, these enzymes may be located in the endoplasmic reticulum (ER), mitochondria, cytosol, lysosomes, or even the nuclear envelope or plasma membrane.