Metabolic Fate of &lt;I&gt;d-cis&lt;/I&gt;-3-Acetoxy-5-[2-(dimethylamino) ethyl]-2, 3-dihydro-2-(&lt;I&gt;p&lt;/I&gt;-methoxyphenyl)-1, 5-benzothiazepin-4 (5H)-one Hydrochloride (CRD-401)

Meshi, Teruhiko; Sugihara, Juko; Sato, Yoshishige

doi:10.1248/cpb.19.1546

Cited by 35 publications

(7 citation statements)

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“…It was assumed that this was a metabolite of diltiazem, although little attempt was made to identify it. Authentic N,O-demethyldesacetyldiltiazem (a metabolite of diltiazem, Meshi et al, 1971;Yabana et al, 1985) had a retention time of 3.1 min when chromatographed in mobile phase and was not extracted from spiked blank serum by hexane/isopropanol. In animals infused with diltiazem at 50 lg kg-' min 'for 180 min, h.p.l.c.…”

Section: Statisticsmentioning

confidence: 99%

“…This study extends previous observations of the effects of diltiazem on the uterus (Abel & Hollingsworth, 1985;1986a,b non-pregnant and late pregnant rats. The elimination clearance of diltiazem is probably due largely to metabolism since negligible concentrations of diltiazem were found in urine and faeces (Meshi et al, 1971). At least 7 metabolites (plus their conjugates) have been detected in urine and bile after oral administration in the rat (Meshi et al, 1971).…”

Section: Statisticsmentioning

confidence: 99%

“…The elimination clearance of diltiazem is probably due largely to metabolism since negligible concentrations of diltiazem were found in urine and faeces (Meshi et al, 1971). At least 7 metabolites (plus their conjugates) have been detected in urine and bile after oral administration in the rat (Meshi et al, 1971). It was concluded that desacetyldiltiazem was a minor metabolite only and that N,O-demethyldesacetyldiltiazem was the main urinary metabolite.…”

Section: Statisticsmentioning

confidence: 99%

“…Hepatic metabolism of drugs has generally been found to show only minor changes during pregnancy (Hytten, 1984;Nau et al, 1984). However, the main system investigated has been the cytochrome P-450-dependent mono-oxygenase system, whereas diltiazem elimination is mainly by deacetylation and demethylation (Meshi et al, 1971). …”

Section: Statisticsmentioning

confidence: 99%

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Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects

Downing

Edwards

Hollingsworth

1987

British J Pharmacology

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1 The kinetics of diltiazem were investigated in ovariectomized (ovx) non-pregnant and intact late pregnant anaesthetized rats following a bolus i.v. injection (2mg kg-') and during a 180 min i.v.infusion (50 fig kg-' min-' and 100 yg kg-min '). Uterine contractions, mean blood pressure and heart rate were measured in the non-pregnant rats. 2 Measurement of serum diltiazem concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: volume of distribution area (V(area)) -256 ± 46 ml; rate constants k,2 -0.46 ± 0.10min-'; k2, -0.09 ± 0.01 min-'; ke1 -0.13 ± 0.03 min-'; elimination clearance -3.2 ± 0.3 mlmin-'; distribution t, (to) -1.4 ± 0.3 min; elimination t, (tio) -61.2 ± 13.0 min. In pregnant rats, a biexponential decay was also observed with similar parameters to those in non-pregnant animals except for markedly increased V(ara) -1004 ± 184 ml; k.1 -0.54 ± 0.16 min-' and elimination clearance -14.8 ± 2.3 mlmin-'.3 Measurement of serum diltiazem concentrations during infusion yielded the following parameters in non-pregnant ovx rats: V(SS) -79 ± 10 ml; rate constants k,2 -1.02 ± 0.21 min-'; k2, -0.03 ± 0.01 min-'; ke1 -0.39 ± 0.06 min '; elimination clearance -7.8 ± 1.2 ml min '. In pregnant rats a marked increase was observed in kel -1.25 ± 0.38 min-' and elimination clearance -36.4 ± 13.8 ml min 4 An immediate reduction in uterine contractions, mean blood pressure and heart rate was observed after bolus i.v. injection of diltiazem with a return towards control values as serum diltiazem concentrations declined. There were significant correlations between the inhibition of the 3 parameters and the log serum concentrations of diltiazem. Serum concentration-response curves indicated IC_, values of 0.5 jpg ml-' for inhibition of uterine contractions, 0.7 pg ml-' for reduction in blood pressure and 1.2 Fg ml-' for reduction in heart rate. There were maintained reductions in the integral of uterine contractions, mean blood pressure and heart rate during infusion. 5 The metabolite desacetyldiltiazem was rarely detected after i.v. bolus injection and was not found in 5/13 rats infused with diltiazem, yet significant inhibition of uterine contractions was observed in all rats. Diltiazem was 3.2 fold more potent than desacetyldiltiazem as an inhibitor of contractions of the rat isolated uterus. 6 These findings indicate that the inhibition of uterine contractions is due to a direct action of diltiazem, and not the metabolite desacetyldiltiazem, and suggest only a slight selectivity for uterine inhibition compared to cardiovascular effects.

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Section: Statisticsmentioning

confidence: 99%

Section: Statisticsmentioning

confidence: 99%

Section: Statisticsmentioning

confidence: 99%

Section: Statisticsmentioning

confidence: 99%

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Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects

Downing

Edwards

Hollingsworth

1987

British J Pharmacology

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“…It is extensively metabolized via O-deacetylation, N-demethylation, O-demethylation, N-oxidation and oxidative deamination, yielding a host of basic and acidic metabolites some of which have potent pharmacological activities (5)(6)(7)(8)(9). For example, it has been shown that the coronary vasodilating potencies of deacetyl OTZ (M1) and N-monodesmethyl OTZ (MA) were approximately 50% and 20%, that of 01Z, respectively (7).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and metabolism of diltiazem in rabbits after a single intravenous or single oral administration

Yeung

Mosher

Pollak

1991

European Journal of Drug Metabolism and Pharmacokinetics

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Diltiazem (DTZ) 5 mg/kg was given to rabbits either orally (n = 5) or intravenously (n = 6). Plasma concentrations and urinary excretion of DTZ and its metabolites were determined by a high performance liquid chromatography assay (HPLC) for 12 and 48 h post dose, respectively. The results showed that the metabolism and disposition of DTZ in rabbits was similar to that of humans, mean absolute bioavailability (F) of DTZ was approximately 30% and the systemic clearance was 64.0 ml/min/kg. The metabolism of DTZ between the two routes of administration was quantitatively different in that higher plasma concentrations of the metabolites were observed after the intravenous dose. This could be a result of incomplete oral absorption, higher clearance of DTZ and the metabolites during the first pass through the liver (i.e. higher sequential first pass effect), and/or extrahepatic metabolism. On the basis of the plasma concentration-time profiles and urinary excretion of DTZ and its metabolites, it is concluded that the rabbit is a suitable animal model to investigate the kinetics and metabolism of DTZ.

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Antihypertensives

Scriabine

Taylor

2000

Ullmann's Encyclopedia of Industrial Chemistry

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Metabolic Fate of <I>d-cis</I>-3-Acetoxy-5-[2-(dimethylamino) ethyl]-2, 3-dihydro-2-(<I>p</I>-methoxyphenyl)-1, 5-benzothiazepin-4 (5H)-one Hydrochloride (CRD-401)

Cited by 35 publications

References 2 publications

Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects

Diltiazem pharmacokinetics in the rat and relationship between its serum concentration and uterine and cardiovascular effects

Pharmacokinetics and metabolism of diltiazem in rabbits after a single intravenous or single oral administration

Antihypertensives

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