A Detailed Evaluation of Promazine Metabolism.

Goldenberg, Harry; Fishman, V. M.; Heaton, Audre M.; Burnett, R. S.

doi:10.3181/00379727-115-29112

Cited by 27 publications

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“…The microsome preparations produced different amounts of promazine 5‐sulphoxide and N ‐desmethylpromazine (Figure 3). As a rule, promazine 5‐sulphoxide was produced in smaller amounts compared to N ‐desmethylpromazine, which is in agreement with earlier investigations on rats (Goldenberg et al ., 1965; Daniel et al ., 1995,1999a,1999b; Syrek et al ., 1997). Interindividual differences in the rates of promazine metabolism were up to three‐fold as high, which agrees with the kinetics parameters in Table 2.…”

Section: Resultssupporting

confidence: 92%

“…During phase I of metabolism, neuroleptics that are phenothiazine derivatives, for example promazine (Figure 1), undergo mainly S‐oxidation in the thiazine ring in position 5 and N‐demethylation in a side chain, as well as aromatic hydroxylation and N‐oxidation (Svendsen & Bird, 1986). In man, N‐demethylation and sulphoxidation were reported to be the dominant pathways of promazine biotransformation (Goldenberg et al ., 1965). Similar promazine metabolism was observed in animals (Weir & Sanford, 1969; Devey et al ., 1981; Daniel et al ., 1995,1999a,1999b; Syrek et al ., 1997).…”

Section: Introductionmentioning

confidence: 99%

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Contribution of human cytochrome P‐450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine

Wójcikowski

Pichard-Garcia

Maurel

et al. 2003

British J Pharmacology

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1 The aim of the present study was to identify human cytochrome P-450 isoforms (CYPs) involved in 5-sulphoxidation and N-demethylation of the simplest phenothiazine neuroleptic promazine in human liver.2 The experiments were performed in the following in vitro models: (A) a study of promazine metabolism in liver microsomesF(a) correlations between the rate of promazine metabolism and the level and activity of CYPs; (b) the effect of specific inhibitors on the rate of promazine metabolism (inhibitors: CYP1A2Ffurafylline, CYP2D6Fquinidine, CYP2A6+CYP2E1Fdiethyldithiocarba-mic acid, CYP2C9Fsulfaphenazole, CYP2C19Fticlopidine, CYP3A4Fketoconazole); (B) promazine biotransformation by cDNA-expressed human CYPs (Supersomes 1A1, 1A2, 2A6, 2B6, 2C9, 2C19, 2E1, 3A4); (C) promazine metabolism in a primary culture of human hepatocytes treated with specific inducers (rifampicinFCYP3A4, CYP2B6 and CYP2C inducer, 2,3,7,8-tetrachlordibenzeno-pdioxin (TCDD)FCYP1A1/1A2 inducer). 3 In human liver microsomes, the formation of promazine 5-sulphoxide and N-desmethylpromazine was significantly correlated with the level of CYP1A2 and ethoxyresorufin O-deethylase and acetanilide 4-hydroxylase activities, as well as with the level of CYP3A4 and cyclosporin A oxidase activity. Moreover, the formation of N-desmethylpromazine was correlated well with S-mephenytoin 4 0 -hydroxylation. 4 Furafylline (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of promazine 5-sulphoxidation, while furafylline and ticlopidine (a CYP2C19 inhibitor) significantly decreased the rate of promazine N-demethylation in human liver microsomes. 5 The cDNA-expressed human CYPs generated different amounts of promazine metabolites, but the rates of CYP isoforms to catalyse promazine metabolism at therapeutic concentration (10 mM) was as follows: 1A142B641A242C943A442E142A642D642C19 for 5-sulphoxidation and 2C1942B641A141A242D643A442C942E142A6 for N-demethylation. The highest intrinsic clearance (V max /K m ) was found for CYP1A subfamily, CYP3A4 and CYP2B6 in the case of 5 -sulphoxidation, and for CYP2C19, CYP1A subfamily and CYP2B6 in the case of N-demethylation. 6 In a primary culture of human hepatocytes, TCDD (a CYP1A subfamily inducer), as well as rifampicin (mainly a CYP3A4 inducer) induced the formation of promazine 5-sulphoxide and Ndesmethylpromazine. 7 Regarding the relative expression of various CYPs in human liver, the obtained results indicate that CYP1A2 and CYP3A4 are the main isoforms responsible for 5-sulphoxidation, while CYP1A2 and CYP2C19 are the basic isoforms that catalyse N-demethylation of promazine in human liver. Of the other isoforms studied, CYP2C9 and CYP3A4 contribute to a lesser degree to promazine 5-sulphoxidation and N-demethylation, respectively. The role of CYP2A6, CYP2B6, CYP2D6 and CYP2E1 in the investigated metabolic pathways of promazine seems negligible.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Contribution of human cytochrome P‐450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine

Wójcikowski

Pichard-Garcia

Maurel

et al. 2003

British J Pharmacology

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“…(64)) [583]. In humans, Ndemethylation and sulphoxidation are the primary metabolic routes of promazine [584]. CYP1A2 and 3A4 are the main enzymes responsible for 5-sulphoxidation of promazine, while CYP1A2 and 2C19 are the major enzymes that catalyse N-demethylation of promazine in human liver [585].…”

Section: Promazinementioning

confidence: 99%

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Zhou¹,

Zhou²,

Liu³

et al. 2009

CMC

147

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Cytochrome P450 2C9 (CYP2C9) is one of the most abundant CYP enzymes in the human liver. CYP2C9 metabolizes more than 100 therapeutic drugs, including tolbutamide, glyburide, diclofenac, celecoxib, torasemide, phenytoin losartan, and S-warfarin). Some natural and herbal compounds are also metabolized by CYP2C9, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Many CYP2C9 substrates are weak acids, but CYP2C9 also has the capacity to metabolise neutral, highly lipophilic compounds. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Data from the site-directed mutagenesis studies have revealed that a number of residues (e.g. Arg97, Phe110, Val113, Phe114, Arg144, Ser286, Asn289, Asp293 and Phe476) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. CYP2C9 is subject to induction by rifampin, phenobarbital, and dexamethasone, indicating the involvement of pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor in the regulation of CYP2C9. A number of compounds have been found to inhibit CYP2C9 and this may provide an explanation for some clinically important drug interactions. Tienilic acid, suprofen and silybin are mechanism-based inhibitors of CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates, inducer or inhibitors of CYP2C9 in drug development and drug discovery scientists should develop drugs with minimal interactions with this enzyme. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.

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Stability, human blood distribution and rat tissue localization of promazine and desmonomethylpromazine

Curry

1989

Biopharm & Drug Disp

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The stability in human blood and urine, partitioning into red blood cells and plasma protein binding of promazine and desmonomethylpromazine were investigated. Tissue localization was investigated in rats. Promazine and desmonomethylpromazine were stable in human plasma and urine for at least 64 days at -20 degrees. The percentage of promazine not bound to protein in plasma was 10.4 +/- 2.43 as estimated by equilibrium dialysis with correction for volume shift, and 11.6 +/- 0.43 per cent as estimated by ultracentrifugation. Data for the mean plasma/red blood cell concentration ratio and the red blood cell/plasma distribution coefficient for promazine were 1.19 +/- 0.13 and 8.21 +/- 0.40, respectively. There was no evidence of time-dependence in plasma/red blood cell partitioning. Ten rat organs and tissues were examined. The concentrations of promazine and desmonemethylpromazine were highest in lung. For promazine, the rank order of tissue localization was lung greater than liver greater than kidney greater than intestine greater than brain greater than spleen greater than red blood cell greater than voluntary muscle greater than plasma greater than stomach greater than heart. For desmonomethylpromazine, the order was reversed in the cases of spleen and brain and interchanged in the cases of stomach and muscle. The brain/plasma concentration ratios for promazine and desmonomethylpromazine in rat were 4.69 and 3.87, respectively.

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A Detailed Evaluation of Promazine Metabolism.

Cited by 27 publications

References 0 publications

Contribution of human cytochrome P‐450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine

Contribution of human cytochrome P‐450 isoforms to the metabolism of the simplest phenothiazine neuroleptic promazine

Substrates, Inducers, Inhibitors and Structure-Activity Relationships of Human Cytochrome P450 2C9 and Implications in Drug Development

Stability, human blood distribution and rat tissue localization of promazine and desmonomethylpromazine

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