CYP isozymes

Azathioprine, mycophenolate mofetil, and enteric-coated MPA are not metabolized through the CYP isozyme system therefore, they do not experience the same DDI profiles as cyclosporine, tacrolimus, and sirolimus. Azathioprine s major DDIs involve allopurinol, angiotensin-converting enzyme (ACE) inhibitors, aminosalicylates (e.g., mesalamine and sulfasalazine), and warfarin.11 The interaction with allopurinol is seen frequently and has clinical significance. Allopurinol inhibits xanthine oxidase, the enzyme responsible for metabolizing azathioprine. Combination of azathioprine and allopurinol has resulted in severe toxicities, particularly myelosuppression. It is recommended that concomitant therapy with azathioprine and allopurinol be avoided, but if combination therapy is necessary, the azathioprine doses must be reduced to one-third or one-fourth of the current dose. Use of azathioprine with the ACE inhibitors or aminosalicylates also can result in enhanced myelosuppression.11 Some case reports exist demonstrating that warfarin s therapeutic effects may be decreased by azathioprine.43-45... 

Extensive metabolism studies carried out mainly in rats and mice show that pyrethroids are metabolized by oxidation and ester cleavage, which are mediated by CYP isoforms and carboxylesterases, respectively. CYP isozymes and carboxylesterases responsible for the metabolism are reviewed below. 

Classification trees are used to predict membership of cases or objects in the classes of a categorical dependent variable from their measurements on one or more predictor variables. Lewis et al. (334) used the concept of classification trees to design a decision tree for human P450 substrates. The intention was to predict which CYP isozyme will interact with which substrates, based on physicochemical parameters. The resulting classifiers are the volume, the... 

Valsartan (2) is a nonheterocyclic antagonist in which the imidazole of losartan has been replaced with an acylated amino acid. It is a very potent ATj antagonist (IC50 =1.6 nM). There is only one metabolite, valeryl 4-hydroxy valsartan, and it is inactive. The enzymes responsible for valsartan metabolism have not been identihed, but do not seem to be P450 CYP isozymes. Food decreases the absorption by 40%. Valsartan (2) is excreted in the bile (70%) and by the kidneys (30%). [See Chiolero and Burnier (1998).]... 

Mirtazapine is demethylated followed by hydroxylation and glucuronide conjugation. Several CYP isozymes are involved in the metabolism of mirtazapine, including 2D6, 3A4, and 1A2. The half-life of mirtazapine is 20-40 hours, and it is usually dosed once in the evening because of its sedating effects. 

Reactive metabolites of xenobiotics may differ in reactivity, and therefore have varying impact on enzymatic activities in terms of proximity to their origin. For example, some intermediates are highly reactive and directly inhibit the enzyme that leads to their formation. These substances are commonly referred to as suicide inhibitors, for obvious reasons. Some suicide inhibitors, such as piperonyl butoxide (PBO), a pesticide synergist) are common inhibitors of certain CYP isozymes. PBO amplifies the toxicity of certain insecticides by inhibiting the insect s CYP enzymes that are involved in its degradation. It is metabolized to a highly reactive carbene, which forms an inhibitor complex with the heme iron of CYP, as shown in Scheme 3.6. 

The antifungal azoles inhibit CYP isozymes and can therefore interact with some statins. 

Multiplicity of Cytochrome P450, Purification, and Reconstitution of Cytochrome P450 Activity. Even before appreciable purification of CYP had been accomplished, it was apparent from indirect evidence that mammalian liver cells contained more than one CYP enzyme. Subsequent direct evidence on the multiplicity of CYPs included the separation and purification of CYP isozymes, distinguished from each other by chromatographic behavior, immunologic specificity, and/or substrate specificity after reconstitution and separation of distinct polypeptides by sodium... 

Although the CYP enzymes are the most abundant in the liver, they are also present in other tissues including the skin, kidney, intestine, lung, placenta, and nasal mucosa. Because CYP exists as multiple isozymes with different substrate specificities, the presence or absence of a particular CYP isozyme may contribute to tissue-specific toxicities. Many drugs and other foreign compounds are known to induce one or more of the CYP isozymes, resulting in an increase, decrease, or an alteration in the metabolic pathway of chemicals metabolized by the CYP isozymes involved. Specific examples of these types of interactions are given later in this section. 

Like some of the CYP isozymes, the expression of some transporters is inducible. Induction of the expression of transporters in response to chemical inducers has been primarily studied in the in vitro models using cell lines derived from animals... 

MultiCASE) (Dearden et al., 1997 Klopman and Rosenkranz, 1994). A further system is Computerized Optimized Parametric Analysis of Chemical Toxicity (COMPACT) (Lewis et al., 1994). The latter analyses the ability of a molecule to fit into the active site of the CYP1A1 isozyme of cytochrome P450 (CYP) (and some other CYP isozymes), by modeling molecular shape (planarity or area/depth) and chemical reactivity (covalent bond formation). The use of COMPACT is limited to molecules that are activated by these CYP enzymes. 

A particular isozyme can perform several types of reaction, including hydroxylations, reductions, O-dealkylations and epoxidations.65 The most important reactions for CAC are hydroxylations and epoxidations. A CYP isozyme can also catalyse different reactions of different substrates. CYP1A, to give an example, can O-dealkylate ethoxyresorufine or hydroxylate benzo[a] pyrene. 

Substrate specificity is reflected in that each CYP isozyme requires different molecular features of its substrates. Thus, CYP2E metabolizes substrates with an alcohol or keto moiety. For CACs, CYP1A1, CYP1A2 and CYP2B are the most important isozymes. CYP1A metabolizes mostly planar substrates like 2,3,7,8-tetrachlorodibenzo-p-dioxin, whereas CYP2B transforms the more globular substrates, e.g. the transformation of the pesticide aldrin into dieldrin. 

The table in (B) provides an overview of different CYP isozymes along with their substrates, inhibitors, and inducers. Obviously, Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms... 

Exposure to two or more chemical agents can result in altered expression of hepatotoxicity. However, qualitatively different interactions may be achieved, depending upon the relative timing of exposures. Simultaneous exposure to competing substrates of a specific CYP isozyme will often slow metabolism and can be protective against reactive metabolite-mediated hepatotoxicity. Alternately, pretreatment with one agent may induce metabolic enzymes that either protect against or potentiate... 

SSRIs inhibit hepatic CYP isozymes and can thereby increase the activity of co-administered drugs that are... 

Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (114). Olanzapine does not inhibit CYP isozymes, and no clinically significant metabolic interaction was found with fluoxetine. 

Citalopram is said to be less likely than other SSRIs to cause drug interactions, because it is a relatively weak inhibitor of CYP isozymes. However, even slight inhibition may have produced serious consequences in this case. 

The authors suggested that since the doses of quetiapine and fluvoxamine were relatively low and since they are metabolized by different CYP isozymes, this was probably not a pharmacokinetic interaction. Instead, they suggested that it may have been caused by dopamine-serotonin disequilibrium. 

---