The liver is a major site for drug metabolism. The goal of metabolism is to produce metabolites that are polar or charged, and can be eliminated by the kidney. Lipid-soluble agents are metabolized by the liver using two general sets of reactions, called phase I and phase II.
Phase I reactions frequently involve the P-450 system. Phase II reactions are conjugations, mostly with glucuronide.
Phase I reactions convert lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group, such as an —OH or —NH2. Most of these reactions utilize the microsomal P-450 enzymes.
Phase I reactions are the basis of a number of drug interactions. There are a whole series of cytochrome P-450 enzymes that can be inhibited or induced. Of these, CYP3A4 plays a role in the metabolism of about 50% of the drugs that are currently prescribed. Inhibition or induction of CYP3A4 by one drug will affect the levels of any other drug that is also metabolized by CYP3A4. For example, rifampin induces CYP3A4 that can increase metabolism of estrogen, thus reducing the effectiveness of birth control pills. Some textbooks include lists of drugs that inhibit or induce CYP3A4. Don’t try to memorize these lists. Be aware of the potential problem and learn the most commonly interacting drugs as you gain experience. There are also known genetic variations in levels of CYP450 enzymes.
Phase II reactions are conjugation reactions. These combine a glucuronic acid, sulfuric acid, acetic acid, or an amino acid with the drug molecule to make it more polar. The highly polar drugs can then be excreted by the kidney.
Renal elimination of drugs involves three physiological processes: glomerular filtration, proximal tubular secretion, and distal tubular reabsorption.
Glomerular filtration: Free drug flows out of the body and into the urine-to-be as part of the glomerular filtrate. The size of the molecule is the only limiting factor at this step.
Proximal tubular secretion: Some drugs are actively secreted into the proximal tubule.
Distal tubular reabsorption: Uncharged drugs may diffuse out of the kidney and escape elimination. Manipulating the pH of the urine may alter this process by changing the ionization of the weak acids and bases. This process was described in Chapter 3 in the context of passive diffusion of drugs across membranes. However, for a drug to be excreted, it needs to be charged so that it is trapped in the urine and can’t cross the membrane to sneak back into the body.
Reminder: When the pH is higher than the pK, the unprotonated forms (A− and B) predominate. When the pH is less than the pK, the protonated forms (HA and BH+) predominate.