N-Dealkylation of tertiary amides by cytochrome P-450

Hall, Larry R.; Hanzlik, Robert P.

doi:10.3109/00498259109039553

Cited by 19 publications

(17 citation statements)

References 19 publications

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“…This pathway is consistent with the previous reports that have demonstrated N-dealkylation of amides or carbamates in the past (Morino et al, 1985;Hall and Hanzlik, 1991;Labroo et al, 1995;Hey and Tolando, 2000). Alternatively, M24 can also undergo dealkylation, which, on oxidation, would result in M1.…”

Section: Dalvie Et Alsupporting

confidence: 82%

Pharmacokinetics, Metabolism, and Excretion of Torcetrapib, a Cholesteryl Ester Transfer Protein Inhibitor, in Humans

Dalvie¹,

Chen²,

Zhang³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics, metabolism, and excretion of torcetrapib, a selective inhibitor of human cholesteryl ester transfer protein, were investigated in healthy human male volunteers after oral administration of [ 14 C]torcetrapib (120-mg dose). The total mean recovery of radiolabeled dose after 21 days was 75.7%, and most of the dose (63%) was excreted in the urine. The total circulating radioactivity and unchanged torcetrapib plasma concentrations increased over the first 6 h and then declined slowly with mean terminal elimination half-lives of 373 and 211 h. Metabolism of torcetrapib was extensive in humans. Only 5.2% of the total dose constituted unchanged torcetrapib in the feces, whereas no parent was excreted unchanged in the urine. Similarly, pharmacokinetic analysis of total radioactivity and unchanged torcetrapib revealed that the area under the concentration versus time curve from zero to infinity of torcetrapib accounted for ϳ7.0% of the circulating radioactivity. Torcetrapib was metabolized to numerous metabolites via oxidation. The primary metabolic pathway involved initial oxidative decarbamoylation followed by extensive further oxidation, resulting in the formation of bistrifluoromethylbenzoic acid (M1) and quinaldic acid (M4) metabolites. A mean 40% of the total dose was excreted in the urine as M4 (and its glucuronide and urea conjugates), whereas 7.0% of the total dose was excreted as M1. In vitro studies using human subcellular fractions suggested that the initial metabolism of torcetrapib proceeds via CYP3A-mediated decarbamoylation. Subsequent oxidations lead to the major circulating and excretory metabolites M1 and M4.Torcetrapib {(Ϫ)-[2R,4S] 4-[(3,5-bis-trifluoromethylbenzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester} was being developed to treat hypercholesterolemia (elevated cholesterol levels) and prevent cardiovascular disease. It was withdrawn from development in 2006 when phase III studies showed excessive mortality in the treatment group receiving a combination of atorvastatin and the study drug (Howes and Kostner, 2007). Torcetrapib acts by inhibiting human cholesteryl ester transfer protein, which normally transfers cholesterol from highdensity lipoprotein (HDL) cholesterol to very-low-density lipoprotein or low-density lipoprotein (LDL). Inhibition of this process results in higher HDL levels (the "good" cholesterol-containing particle) and reduces LDL levels (the "bad" cholesterol) (Clark et al., 2006). Administration of torcetrapib alone or in combination with atorvastatin led to an increase in HDL and a decrease in LDL concentrations (Brousseau et al., 2004;Clark et al., 2004;McKenney et al., 2006).The pharmacokinetics of torcetrapib has been evaluated in the rat and monkey. The results from these studies have indicated that the drug was moderately absorbed with a bioavailability of 33 to 45% and readily distributed throughout the body (volume of distribution is 1.1-2.5 l/kg). The clearance of torcetrapib i...

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Section: Dalvie Et Alsupporting

confidence: 82%

Pharmacokinetics, Metabolism, and Excretion of Torcetrapib, a Cholesteryl Ester Transfer Protein Inhibitor, in Humans

Dalvie¹,

Chen²,

Zhang³

et al. 2008

Drug Metab Dispos

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“…28 In contrast, large intramolecular hydrogen isotope effects ( 2 k/ 1 k > 7) observed during the oxidation of amides provided evidence that the C-H bond was initially cleaved. 18,21,29 Further, N-demethylation of dimethylanilines by P450 enzymes showed similar hydrogen isotope effect profiles as for H-atom abstraction by tert-butoxy radicals 17,30 suggesting a HAT mechanism as the initial step. However, hydrogen isotope effects are often masked by rate determining steps other than the C-H cleavage and may show a rather large variability even in the absence of masking.…”

Section: Introductionmentioning

confidence: 84%

Cytochrome P450-catalyzed dealkylation of atrazine byRhodococcussp. strain NI86/21 involves hydrogen atom transfer rather than single electron transfer

et al. 2014

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Cytochrome P450 enzymes are responsible for a multitude of natural transformation reactions. For oxidative N-dealkylation, single electron (SET) and hydrogen atom abstraction (HAT) have been debated as underlying mechanisms. Combined evidence from (i) product distribution and (ii) isotope effects indicate that HAT, rather than SET, initiates N-dealkylation of atrazine to desethyl- and desisopropylatrazine by the microorganism Rhodococcus sp. strain NI86/21. (i) Product analysis revealed a non-selective oxidation at both the αC and βC-atom of the alkyl chain, which is expected for a radical reaction, but not SET. (ii) Normal (13)C and (15)N as well as pronounced (2)H isotope effects (εcarbon: -4.0‰ ± 0.2‰; εnitrogen: -1.4‰ ± 0.3‰, KIEH: 3.6 ± 0.8) agree qualitatively with calculated values for HAT, whereas inverse (13)C and (15)N isotope effects are predicted for SET. Analogous results are observed with the Fe(iv)[double bond, length as m-dash]O model system [5,10,15,20-tetrakis(pentafluorophenyl)porphyrin-iron(iii)-chloride + NaIO4], but not with permanganate. These results emphasize the relevance of the HAT mechanism for N-dealkylation by P450.

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“…Although such a hydrolysis reaction is a wellknown metabolic fate of amides (11,12), this reaction was not seen in rats or in man (6). In the rat, the ethyl groups of the N,N-diethylamide structure were deaJkylated, obviously through a P-45O-catalyzed c.o-l oxidation (13). This was the major phase I metabolic reaction in rats (6).…”

Section: Discussionmentioning

confidence: 99%

Identification of major urinary metabolites of the catechol-O-methyltransferase inhibitor entacapone in the dog

Wikberg

Ottoila

Taskinen

1993

European Journal of Drug Metabolism and Pharmacokinetics

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Metabolites of entacapone, (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl) propenamide, a potent inhibitor of catechol-O-methyltransferase, were isolated from dog urine. After hydrolysis of glucuronides and sulfates, 5 metabolites were identified in addition to unchanged entacapone by HPLC with diode-array UV detection, electron ionization mass spectrometry and IR spectroscopy. The (Z)-isomer of entacapone was the most abundant phase I metabolite while less abundant metabolites were formed through cleavage or reduction of the side chain carbon-carbon double bond, hydrolysis of the amide bond or through hydration of the nitrile group. The most abundant urinary metabolites were glucuronides. The glucuronidation site of these ortho-nitrocatechols was shown to be the hydroxyl meta to the nitro group.

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N-Dealkylation of tertiary amides by cytochrome P-450

Cited by 19 publications

References 19 publications

Pharmacokinetics, Metabolism, and Excretion of Torcetrapib, a Cholesteryl Ester Transfer Protein Inhibitor, in Humans

Pharmacokinetics, Metabolism, and Excretion of Torcetrapib, a Cholesteryl Ester Transfer Protein Inhibitor, in Humans

Cytochrome P450-catalyzed dealkylation of atrazine byRhodococcussp. strain NI86/21 involves hydrogen atom transfer rather than single electron transfer

Identification of major urinary metabolites of the catechol-O-methyltransferase inhibitor entacapone in the dog

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