Cytochrome P450 isoenzymes

Metabolism is still a barrier to be overcome. Some QSAR, pharmacophore, protein, and rule-based models are available to predict substrates and inhibitors of a specific cytochrome P450 isoenzyme [47-55]. 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

CYP. cytochrome P450 isoenzyme HIV, human immunodeficiency vims INR, International Normalized Ratio LFTs, liver function tests MAOI, monoamine oxidase inhibitor PT, prothrombin time TCA, tricyclic antidepressant. 

P. H., Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues, J. Pharmacol. Exp. Then 1990, 253, 387-394. 

By using in vitro preparations of human enzymes it is possible to predict those antibiotics that will adversely affect the metabolism of other drugs [110]. Such studies have shown that rifaximin, at concentrations ranging from 2 to 200 ng/ml, did not inhibit human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 [34], In an in vitro hepatocyte induction model, rifaximin was shown to induce cytochrome P450 3A4 (CYP3A4) [34], an isoenzyme which rifampicin is known to induce [109],... 

The answer is d. (Kai ung, p 505.) Fluoxetine is a highly selective serotonin re uptake inhibitor (55RI) acting on the 5-1 IT transporter. It forms an active metabolite that is effective for several days. Selective serotonin reuptake inhibitors are inhibitors of cytochrome P450 isoenzymes, which is the basis of potential drug-drug interactions... 

Chang GW, Kam PC. 1999. The physiological and pharmacological roles of cytochrome P450 isoenzymes. Anaesthesia 54 42-50. 

The cytochrome P450 system is actually a family of related liver enzymes. Each specific enzyme within this family is called an isoenzyme. New isoenzymes within the cytochrome P450 system are constantly being discovered. The 1A2, 2C9/2C19, 2D6, and 3A4 isoenzymes are the best understood. Table 3.10 shows the impact of the newer antidepressants on particular cytochrome P450 isoenzymes and the drugs that may be affected. 

Walton et al. (2001a) examined data for compounds eliminated by the cytochrome P450 isoenzymes CYP1A2 in humans. Absorption, bioavailabihty, and route of excretion were generally similar between humans and the test species for each of the substances (caffeine, paraxanthine, theobromine, and theophylline). However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceeded the fourfold default factor for toxicokinetics, whereas the rabbit (2.6) and the dog (1.6) were below this value. 

Nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). 

Liver microsomes have shown that zileuton and its N-dehydroxylated metabolite can be oxidatively metabolized by the cytochrome P450 isoenzymes 1A2, 2C9, and 3A4. Use caution when prescribing a medication that inhibits any of these enzymes. 

Aprepitant is a moderate CYP3A4 inhibitor. Aprepitant should not be used concurrently with pimozide or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. Aprepitant is contraindicated in patients who are hypersensitive to any component of the product. 

In vitro studies showed that dexmethylphenidate did not inhibit cytochrome P450 isoenzymes. 

Pharmacokinetic (PK) studies in different animal species and additional in vitro studies provide information on the compound s predicted human PK parameters, including dose- and time-dependencies, its protein binding, the effect of food on its PK, and the cytochrome P450 isoenzymes responsible for its metabolism as well as the stmcture and activity of the main metabolites. Also a sensitive assay to quantify the compound and its metabolites in human blood and urine should have been developed and validated. 

The taxanes are practically insoluble in water and solubility is limited to mixtures of ethanol with poly-ethoxylated castor oil. They are generally administered in 3-24 hour infusions. The taxanes are for 90-95% plasma protein bound and primarily metabolized by P450 enzymes in the liver. Less than 10% is excreted in the urine as parent compounds. The elimination half-life of docetaxel is approximately 10 hours while that of paclitaxel has been vary-ingly reported between 5 and 50 hours. Inhibitors of the cytochrome P450 isoenzyme Cyp3A4, like keto-conazole and erythromycine, are contraindicated. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Changes in protein binding Changes in hepatic enzymes and drug metabolism (e.g., hepatic cytochrome P450 isoenzymes)... 

Memantine is not a major substrate for hepatic cytochrome P450 isoenzymes and has not been shown to significantly inhibit or induce these enzymes. However, memantine is partially excreted by renal tubular secretion. Thus, concomitant use of other medications that use the same renal system (i.e., triampterene, hydrochlorothiazide, digoxin, cimetidine, ranitidine, metformin, and quinidine) may affect plasma levels of both drugs (Namenda 2005). Memantine should not be used in combination with other NMDA receptor antagonists, such as amantadine or dextromethorphan, because these combinations have not been formally studied. The clearance of memantine can be reduced when the urine is alkalinized, such as with the concomitant use of sodium bicarbonate or carbonic anhy-... 

Acceptable drug metabolism and interaction profiles based on microsomal and recombinantly expressed cytochrome P450 isoenzyme studies Recent addition Toxicogenomic data for early assessment of alteration in expression of RNA transcripts (and therefore proteins) related to toxic responses so that modification of safer and more potent variants of NME could be made and identified early... 

Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%. The plasma concentrations are proportional up to 800 mg orally. Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours. There are no active metabolites and protein binding is minimal. Lacosamide does not induce or inhibit cytochrome P450 isoenzymes, so drug interactions are negligible. 

Wang, R.-S., Nakajima, T., Park, S.S., Gelboin, H.V Murayama, N. (1993) Monoclonal anti-body-directed assessment of toluene induction of rat hepatic cytochrome P450 isoenzymes. Biochem. Pharmacol., 46, 413 419... 

Several sex-dependent differences have been observed in the action of cytochrome P450 isoenzymes on steroid hormones.290 2903 Thus, androstenedione is hydroxylated by rat liver enzymes specific for the 60, 7a, 16a, and 160 positions.291 Of these the 16 hydroxylase is synthesized only in males, and synthesis of the 6 hydroxylase is also largely suppressed in females. 

Zaleplon is metabolized primarily by aldehyde oxidase to form 5-oxo-zaleplon and, to a lesser extent, by the cytochrome P450 isoenzyme CYP3A4 to desethylzaleplon, which is further metabolized by aldehyde oxidase to 5-oxo-desethylzaleplon [25]. 

Zaleplon is primarily metabolized by aldehyde oxidase and use with inhibitors of this enzyme, such as cimetidine, may result in increased plasma concentrations of zaleplon. Zaleplon is also partly metabolized by the cytochrome P450 isoenzyme CYP3A4 and, consequently, caution is advised when zaleplon is given with drugs that are substrates for, or potent inhibitors of, this isoenzyme. Cimetidine is also an inhibitor of CYP3A4 and thus inhibits both the primary and secondary metabolic pathways of zaleplon. Use with rifampicin or other potent enzyme-inducing drugs may accelerate the metabolism of zaleplon and reduce its plasma concentrations [40]. 

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