3

Essentials in Pharmacology: Drug Metabolism, Cytochrome P450 Enzyme System, and Prescription Writing

DRUG METABOLISM OVERVIEW

The liver is the main site for drug metabolism. Drug metabolism often enhances termination of drug action, but on occasion metabolism can lead to bio-activation, as with prodrugs. The drug metabolism process basically introduces hydrophilic functionalities onto the drug molecule to facilitate excretion. When the drug molecule is oxidized, hydrolyzed, or conjugated, the whole molecule becomes more hydrophilic and is excreted more easily.

The liver enzymes induce two drug metabolism pathways known as Phase I and Phase II. These phases are dependent on two factors: hepatic blood flow and metabolic capacity of the liver.

Typical Phase I metabolism includes oxidation and hydrolysis. The microsomal enzymes or cytochromes involved in Phase I reactions are primarily located in the endoplasmic reticulum of the liver cells. Phase I metabolites that are hydrophilic (more water soluble) are readily excreted, and all other metabolites undergo a subsequent Phase II metabolism. The capacity of the liver to metabolize drugs by the Phase I enzyme systems is compromised when the liver is in failure. The metabolic capacity of the liver has to be decreased by more than 90%, before drug metabolism is significantly affected. Phase II metabolism includes glucuronidation and glutathione conjugation of the drug molecule, thus making the drug hydrophilic and ready for excretion. Phase II occurs after Phase I metabolism, and often drugs undergo both Phase I and Phase II metabolism prior to excretion. It is important to note that Phase II can occur independent of Phase I metabolism and Phase II metabolism can still occur even in end-stage liver failure.

Although the liver is the primary site for metabolism, virtually all tissue cells have some metabolic activities. Other organs with significant metabolic activities include the gastrointestinal tract, kidneys, and lungs. When a drug is given orally, it undergoes metabolism in the GI tract and the liver before reaching the systemic circulation. This process is called first-pass metabolism. First-pass metabolism limits the oral bioavailability of drugs, sometimes quite significantly. During the first-pass metabolism, after a drug is ingested, it reaches the liver through the hepatic portal system before it reaches the rest of the body. Often, the liver metabolizes these drugs to such an extent that only a small amount of active drug emerges from the liver to enter the systemic circulation. This first pass through the liver thus greatly reduces the bioavailability of the drug. When ingested orally, the first-pass effect of a drug can also be affected by the enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial enzymes, and hepatic enzymes. Thus the drug can be given by alternate routes (IM/IV) if this effect is to be bypassed.

The first-pass effect can be beneficial in some cases, as with prodrugs such as codeine, which gets activated to morphine by first-pass metabolism. Therefore, in this case, Phase I oxidation converts a pharmacologically inactive compound to a pharmacologically active one. Drugs often undergo both Phase I and II reactions before excretion.

CYTOCHROME ENZYME SYSTEM OVERVIEW

Cytochrome P450 refers to a group of heme-containing enzymes that are primarily located in the liver hepatocytes and within the enterocytes in the small intestine. These enzymes are important for drug biotransformation, drug metabolism, and detoxification of endogenous compounds after they have been ingested. This accounts for the high concentrations of these enzymes in the liver and small intestine.

Infants develop a mature hepatic CYP450 enzyme system in the two weeks following birth. CYP450 activity can be temporarily depressed by fulminant infections, or the activity may be affected long term due to celiac disease or cirrhosis of the liver. The elderly may also have a decrease in hepatic CYP450 metabolic activity because of changes in liver blood flow, size, or drug binding and drug distribution with age. The P450 system can be altered by a number of mechanisms, including inhibition and induction, and can vary from person to person. Knowledge of the P450 system is critical in understanding drug metabolism and drug interactions.

Cytochrome P450 Enzyme Nomenclatures

Current nomenclature of the cytochrome P450 (CYP) enzymes is three-tiered: CYP followed by a number, representing the enzyme family, followed by a letter representing the subfamily, and then followed by another number representing the individual gene: for example, CYP3A4.

Each enzyme is termed an “isoform” or “isoenzyme.” CYP450 enzyme system has eight main P450 isoform groups: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. CYP2D6 and CYP3A4 are two of the most common enzymes, with the CYP3A4 isoform being the most abundant cytochrome family expressed in the human liver and intestine. Thus CYP3A4 is involved in the metabolism of a greater number of drugs, and consequently a greater proportion of adverse drug-drug interactions (DDIs), than the other CYP isoforms.

As stated previously, CYP enzymes are involved in the oxidative metabolism of a number of drug classes and endogenous substances, including prostaglandins and steroid hormones. Drugs may affect or be affected by one or several isoenzymes, thus accounting for the significant complexity associated with the metabolism of many medications. Cytochrome P450 enzymes metabolize drugs, toxins, and other substances, so they can be safely eliminated from the body. CYP enzymes eliminate drugs by making them water-soluble through a first-phase oxidation process, and if the drug is not completely transformed for elimination, then a second metabolic phase—the conjugation-reaction phase—is triggered to make the drug water-soluble. CYP enzymes account for elimination of commonly prescribed drugs: benzodiazepines, beta-blockers, calcium channel blockers, opioids, statins, selective serotonin reuptake inhibitors (SSRIs), and warfarin (Coumadin), to name a few.

CYP2D6 and CYP2C19 genetic polymorphisms: Of Caucasians, 6–10% are CYP2D6 deficient, whereas others may have high levels of the enzyme. Polymorphism of the gene encoding this enzyme leads to clinical phenotypes showing either extensive or poor drug metabolism. Genetic polymorphism also exists for CYP2C19 expression, affecting 3–5% of Caucasians and 15–20% of Asians. These individuals have no CYP2C19 function, and individuals of Asian and African decent are more likely to be poor metabolizers.

CYP System-Related Terminologies

Substrate: A substrate is a drug or compound on which a particular enzyme acts to metabolize the drug. For example, protease inhibitors idinavir (Crixivan), nelfinivir (Viracept), ritonavir (Norvir), and saquinavir (Fortovase) are substrates for the isoform CYP3A4 and therefore are metabolized by CYP3A4.

Do not concurrently prescribe two substrates competing for the same enzyme, as one drug may inhibit or induce metabolism of the other, and an adverse drug interaction may occur. For example, ethanol and acetaminophen (Tylenol) are substrates for CYP2E1; thus when the two are combined, ethanol can adversely affect the metabolism of acetaminophen by causing increased NAPQI production. Hence alcoholics can overdose with a therapeutic dose of Tylenol.

Inducer: An inducer of a specific CYP450 isoform increases the amount and subsequent activity of that particular enzyme in the hepatic and small intestinal tissues, thus causing increased clearance of the substrate. This can potentially lead to diminished plasma levels of the active drug that is a substrate for that enzyme. In HIV patients on protease inhibitors, the simultaneous use of the herbal antidepressant St. John’s wort significantly decreases blood levels and the antiviral efficacy of the protease inhibitors. This is because St. John’s wort is a potent inducer of CYP3A4.

Inhibitor: An enzyme inhibitor reduces the activity of a specific cytochrome P450 isoform to metabolize the substrate, resulting in an accumulation from decreased clearance of the substrate. The toxicity typically seen is identical to what would be seen from an overdose of the substrate drug.

With regard to CYP3A4, it is not just drugs that can inhibit this isoform; it can also be affected by grapefruit juice. Bergamottin, a furan-coumarin, and possibly some other related compounds found in grapefruit juice, both inhibit the action of CYP3A4 and reduce hepatic and intestinal concentrations of CYP3A4, causing the accumulation of a number of CYP3A4 substrates. The ability of grapefruit to lead to excessive plasma concentrations of CYP3A4 substrates was first encountered with calcium channel blockers, where excessive blood levels led to hypotension and peripheral edema.

Drug Transporters

In addition to the CYP enzyme system, metabolism of certain medications can also be affected by transporter proteins that actively transport medications into and out of cells. These transporter proteins are found in various tissues and organs, located on the luminal side of the enterocytes in the small intestines, renal tubular cells, the bile canaliculi, adrenal glands, and on the luminal surface of capillary endothelial cells in the brain. Drug transporters help control access of drugs to the systemic circulation by dictating the amount of drug that can enter the body from the gut lumen. Therefore, they influence how much drug escapes first-pass metabolism in both the gut and the liver.

Transporter proteins are influx or efflux pumps. The influx, or uptake, pumps transport drugs into cells, and the efflux pumps transport drugs out of cells. Efflux pumps control the amount of drug inside a cell. Organic anion transporting polypeptide (OATP) and organic cation transporting polypeptide (OCTP) are examples of uptake transporters. P-glycoprotein (P-gp) is an example of an ATP-dependent efflux transporter that takes drug molecules from the cells and transports the drugs back into the intestinal lumen for excretion. P-gp thus affects how drugs are absorbed, distributed, and eliminated by the body. By transporting many drugs that are substrates of CYP3A4, P-gp helps regulate the amount of drug molecules in the enterocyte, thus preventing CYP3A4 saturation. CYP3A4 concentrations decrease and P-gp concentrations increase from the proximal to distal portions of the gut. P-gp inhibitor drugs will increase the bioavailability of a P-gp substrate by slowing drug excretion, and a P-gp inducer will reduce the bioavailability of a substrate drug by speeding up the elimination of the drug.

Digoxin (Lanoxin) is a P-gp substrate and is independent of CYP3A4 action. P-gp inhibits the bioavailability of digoxin and facilitates the renal and biliary secretion of digoxin. Erythromycin (E-Mycin) or clarithromycin (Biaxin), when given to patients on chronic digoxin, cause an increase in serum digoxin concentrations, as they are potent P-gp inhibitors. Azithromycin (Zithromax) appears to have little influence on P-gp-mediated digoxin absorption or excretion and would be the safest macrolide to use concurrently with oral digoxin.

Hence ATP-dependent efflux drug transporter P-glycoproteins affect how drugs are absorbed, distributed, and eliminated by the body. P-gp and CYP3A4 are present in the gut, and this accounts for why some DDIs occur first in the gastrointestinal tract and then in the liver. Drug interactions occurring through CYP isoenzymes, also most often involve the P-glycoprotein (P-gp) transporter system. Many P-gp inhibitors are CYP3A4 inhibitors too.

P-gp substrates: acyclovir (Zovirax) amiodarone (Cordarone), amitriptyline (Elavil), amoxocillin (Amoxil), ampicillin (Omnipen), digoxin (Lanoxin), loperamide (Diamode), methotrexate (Rheumatrex), quinidine (Quinidine Gluconate), valacyclovir (Valtrex), and vinblastine (Velban).

P-gp inhibitors: cyclosporine (Sandimmune), erythromycin (E-Mycin), clarithromycin (Biaxin), iatroconazole (Sporanox), ketoconazole (Nizoral), nelfinavir (Viracept), quinidine (Quinidine Gluconate), reserpine (Serpalan), ritonavir (Norvir), saquinavir (Invirase), tacrolimus (Prograf), and verapamil (Calan).

P-gp inducers: barbiturates, rifampin (Rifadin), and St. John’s wort.

Many of the drugs typically encountered in dentistry are substrates, inducers, or inhibitors of the CYP450 enzyme system and can be associated with adverse DDIs. Knowing what drugs your patient takes for underlying disease states can help you prevent the occurrence of DDIs by prescribing a drug that does not impact the P450 isoform involved in the metabolism of drugs the patient consumes routinely.

The substrates, inhibitors, and inducers of the eight most common CYP450 isoenzymes are listed in the following sections. Drugs commonly prescribed in the dental setting, or drugs of importance to the dental setting, have been highlighted in the text following and in Table 3.1.

Table 3.1 Specific CYP Isoenzymes Affecting Drugs Commonly Encountered in Dentistry

< ?vsp 3pt?>

< ?vsp 3pt?>

< ?vsp 3pt?>

< ?vsp 3pt?>

< ?vsp 3pt?>

< ?vsp 3pt?>

< ?vsp 3pt?>

< ?vsp 3pt?>

< ?vsp 3pt?>