Thought to be same as CYP1A2 Amiodarone, fluoroquinolone antibiotics, fluvoxamine Tranylcypromine, methoxsalen Efavirenz, nelfinavir, ritonavir Probably similar to CYP2C9 Amiodarone, fluconazole, fluvastatin, lovas-
tatin, zafirlukast Cimetidine, ketoconazole, omeprazole, ticlo-pidinea
Amiodarone, cimetidine, fluoxetine, paroxe-
tine, quinidine Disulfiram"
HIV antivirals (e.g., Ritonavir), amiodarone, cimetidine, diltiazem, erythromycin", grapefruit juice, ketoconazole Thought to be same as CYP3A4 Unclear at this time but may be similar to CYP3A4
"Mechanism-based inactivator. CYP, cytochrome P450.
Enzyme inhibition is the most frequently observed result of CYP modulation and is the primary mechanism for drug-drug pharmacokinetic interactions. The most common type of inhibition is simple competitive inhibition, wherein two drugs are vying for the same active site and the drug with the highest affinity for the site wins out. In this scenario, addition of a second drug with greater affinity for the enzyme inhibits metabolism of the primary drug, and an elevated primary drug blood or tissue concentration is the result. In the simplest case, each drug has its own unique degree of affinity for the CYP enzyme active site, and the degree of inhibition depends on how avidly the secondary (or effector) drug binds to the enzyme active site. For example, ketocona-zole and triazolam compete for binding to the CYP3A4 active site and thus exhibit their own unique rate of metabolism. However, when given concomitantly, the metabolism of triazolam by the CYP3A4 enzyme (essentially the only enzyme that metabolizes triazolam) is decreased to such a degree that the patient is exposed to 17 times as much of parent triazolam as when keto-conazole is not present. Table 4.3 lists the common CYP isoforms and representative inhibitory agents.
A second type of CYP enzyme inhibition is mechanism-based inactivation (or suicide inactivation). In this type of inhibition, the effector compound (i.e., the in hibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme and prevents any further metabolism by the enzyme. This mechanism-based inactivation lasts for the life of the enzyme molecule and thus can be overcome only by the proteolytic degradation of that particular enzyme molecule and subsequent synthesis of new enzyme protein. A drug that is commonly used in clinical practice and yet is known to be a mechanism-based inactivator of CYP3A4 is the antibiotic erythromycin.
Induction of drug-metabolizing activity can be due either to synthesis of new enzyme protein or to a decrease in the proteolytic degradation of the enzyme. Increased enzyme synthesis is the result of an increase in messenger RNA (mRNA) production (transcription) or in the translation of mRNA into protein. Regardless of the mechanism, the net result of enzyme induction is the increased turnover (metabolism) of substrate. Whereas one frequently associates enzyme inhibition with an increase in potential for toxicity, enzyme induction is most commonly associated with therapeutic failure due to inability to achieve required drug concentrations.
Table 4.4 lists representative inducers of each of the CYP isoforms. No inducers of CYP2D6 have been identified.
L TABLE 4.4 Representative Inducers for Each of the CYP Isoforms Involved in Human Drug Metabolism
CYP Isoform Examples of Inducers
CYP1A1 Smoking (polycyclic aromatic hydrocarbons), char-grilled meat, omeprazole CYP1A2 Same as CYP1A1
CYP2A6 Phenobarbital, dexamethasone
CYP2B6 Phenobarbital, dexamethasone, rifampin
CYP2C8 Same as CYP2C9
CYP2C9 Rifampin, dexamethasone, phenobarbital
CYP2C19 Rifampin CYP2D6 None known
CYP2E1 Ethanol, isoniazid
CYP3A4 Efavirenz, nevirapine, barbiturates, carba-
mazepine, glucocorticoids, phenytoin, pioglitazone, rifampin, St. John's wort CYP3A5 Thought to be same as CYP3A4
The time course of enzyme induction is important, since it may play a prominent role in the duration of the effect and therefore the potential onset and offset of the drug interaction. Both time required for synthesis of new enzyme protein (transcription and translation) and the half-life of the inducing drug affect the time course of induction. An enzyme with a slower turnover rate will require a longer time before induction reaches equilibrium (steady state), and conversely, a faster turnover rate will result in a more rapid induction. With respect to the drug inducer, drugs with a shorter halflife will reach equilibrium concentrations sooner (less time to steady state) and thus result in a more rapid maximal induction, with the opposite being true for drugs with a longer half-life.
The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1-5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins.
CONJUGATIVE ENZYMES: PHASE II REACTIONS
Phase II conjugative enzymes metabolize drugs by attaching (conjugating) a more polar molecule to the original drug molecule to increase water solubility, thereby permitting more rapid drug excretion. This conjugation can occur following a phase I reaction involving the molecule, but prior metabolism is not required. The phase II enzymes typically consist of multiple iso-forms, analogous to the CYPs, but to date are less well defined.
Glucuronosyl transferases (UGTs) conjugate the drug molecule with a glucuronic acid moiety, usually through establishment of an ether, ester, or amide bond. Examples of each of these types of conjugates are presented in Figure 4.1. The glucuronic acid moiety, being very water soluble, generally renders the new conjugate more water soluble and thus more easily eliminated. Typically this conjugate is inactive, but sometimes it is active. For example, UGT-mediated conjugation of morphine at the 6- position results in the formation of morphine-6-glucuronide, which is 50 times as potent an analgesic as morphine.
It is now apparent that UGTs are also a superfamily of enzyme isoforms, each with differing substrate specificities and regulation characteristics. Of the potential products of the UGT1 gene family, only expression of UGT1A1, 3, 4, 5, 6, 9 and 10 occurs in humans. Depending on the isoform, these enzymes have varying reactivity toward a number of pharmacologically active compounds, such as opioids, androgens, estrogens, progestins, and nonsteroidal antiinflammatory drugs; UGT1A1 is the only physiologically significant enzyme involved in the conjugation of bilirubin. UGT1A4 appears to be inducible by phenobarbital administration, and UGT1A7 is induced by the chemopreventive agent oltipraz.
UGT2B7 is probably the most important of the UGT2 isoforms and possibly of all of the UGTs. It exhibits broad substrate specificity encompassing a variety of pharmacological agents, including many already mentioned as substrates for the UGT1A family. Little is known about the substrate specificities of the other UGT2B isoforms or the inducibility of this enzyme family.
As their name implies, the N-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. Examples of this type of reaction are depicted in Figure 4.1. The net result of this conjugation is an increase in water solubility and increased elimination of the compound. The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2. Little overlap in substrate specificities of the two isoforms appears to exist. NAT-2 is a polymorphic enzyme, a
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