Species differences in the disposition and metabolism of camazepam

Morino, Akira; Nakamura, Akio; Nakanishi, Kotoyoshi; Tatewaki, Nobukiyo; Sugiyama, Makoto

doi:10.3109/00498258509049098

Cited by 10 publications

(2 citation statements)

References 12 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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“…The names of drug and drug‐like compounds and related data are listed in Table 1 and 2. The absorption data was collected and evaluated from 244 papers 1–5, 8–12, 18–251. The following information concerning human drug absorption was recorded from the literature: absorption data given from the literature;oral bioavailability or absolute bioavailability;percentage of cumulative urinary excretion of unchanged drug and its metabolites following oral and intravenous administration;percentage of metabolites in urine or first‐pass effect following oral and intravenous administration;percentage of unchanged drug in urine following oral and intravenous administration;percentage of excretion of drug in bile following oral and intravenous administration;percentage of cumulative excretion of drug in feces following oral and intravenous administration;total recovery of drug in urine and feces following oral and intravenous administration;single dose level in mg or mg/kg and daily oral dose in mg. …”

Section: Methodsmentioning

confidence: 99%

Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure–activity relationship (QSAR) with the Abraham descriptors

Zhao

Abraham

et al. 2001

Journal of Pharmaceutical Sciences

484

369

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N,N‐dimethylcarbamyl derivatives of oxazepam

Yang

1991

Chirality

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Three N,N-dimethylcarbamyl derivatives of oxazepam (1-(N,N-dimethylcarbamyl)oxazepam, 3-O-(N,N-dimethylcarbamyl)oxazepam, and 1,3-O-bis(N,N-dimethylcarbamyl) oxazepam) and a 3-O-acyl-1-(N,N-dimethylcarbamyl)-oxazepam were synthesized from either oxazepam or demoxepam. Enantiomeric pairs of these derivatives and of camazepam were resolved by high-performance liquid chromatography on at least two of three commercially available chiral stationary phase columns employed. Absolute configurations of resolved enantiomers were established by comparing their circular dichroism spectra to those of enantiomeric oxazepams with known absolute stereochemistry. Similar to those of oxazepam, enantiomers of 1-(N,N-dimethylcarbamyl)oxazepam undergo rapid racemization (t1/2 1.9 min at 23 degrees C and 0.9 min at 37 degrees C) in an aqueous solution at pH 7.5. The (R)-enantiomer of rac-3-O-acyl-1-(N,N-dimethylcarbamyl)oxazepam was hydrolyzed approximately 4.6-fold faster than the (S)-enantiomer by esterases in rat liver microsomes, whereas the (S)-enantiomer was hydrolyzed approximately 43-fold faster than the (R)-enantiomer by esterases in rat brain S9 fraction.

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Species differences in the disposition and metabolism of camazepam

Cited by 10 publications

References 12 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

Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure–activity relationship (QSAR) with the Abraham descriptors

N,N‐dimethylcarbamyl derivatives of oxazepam

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