Adsorptive stripping voltammetric determination of antihypertensive agent: diltiazem.

Adsorptive stripping voltammetry was used to determine the antihypertensive agent diltiazem in phosphate buffer (pH 7.0). The adsorptive cathodic peak was observed at -1.72 V vs. Ag/AgCl. The peak response was characterized with respect to pH, preconcentration time, possible interferences, accumulation potential and supporting electrolytes. The obtained results were analyzed and the statistical parameters were calculated. The proposed method was applied to determine the mentioned drug in pharmaceutical formulation (capsule) and urine. The detection limit is 1x10(-8) M (4.5 ng ml(-1)) using 180 s preconcentration time, whereas the lower limit of detection is 6x10(-9) M (2.7 ng ml(-1)).

Diltiazem and pentoxifylline determination in postmortem specimens.

A 78-year-old woman was found dead in her basement. Qualitative screening of available postmortem specimens detected the presence of diltiazem and pentoxifylline. Quantitations were carried out by gas chromatography using nitrogen-phosphorus detection and confirmed by gas chromatography-mass spectrometry with the following results: blood, 0.59 mg/dL diltiazem and 0.63 mg/dL pentoxifylline; urine, 1.17 mg/dL diltiazem and 0.08 mg/dL pentoxifylline; bile, 0.40 mg/dL diltiazem and 0.22 mg/dL pentoxifylline; gastric contents, 0.28 mg/dL diltiazem and 0.02 mg/dL pentoxifylline. Both drugs were found qualitatively in formaline-fixed tissues.

A possible suicide by diltiazem overdose.

This report describes a possible suicide by overdosage with diltiazem. The decreased, a 39-year-old male who had been under treatment for an unidentified heart condition, was discovered on the bathroom floor in his residence. Comprehensive drug screens performed on available postmortem specimens revealed the presence of 6.9 mg/L diltiazem, 0.182 g/100 mL ethanol, and a trace of propranolol in blood, and 4.7 mg/L diltiazem and 0.251 g/100 mL ethanol in urine.

Metabolism of clentiazem in rats.

Following oral dosing of [14C]clentiazem to rats the metabolites in urine and bile were separated and their chemical structures were investigated by HPLC and GC-MS analyses. Fifteen basic, 6 acidic, 2 neutral and 4 conjugated metabolites were found in urine and/or bile. Eight basic metabolites (MB1-8) were identified as the synthetic compounds; deacetyl clentiazem (MB1), N-monodemethyl clentiazem (MB2), deacetyl-N-monodemethyl clentiazem (MB3), deacetyl-O-demethyl clentiazem (MB4), N-monodemethyl-O-demethyl clentiazem (MB5), deacetyl-N-monodemethyl-O-demethyl clentiazem (MB6), O-demethyl clentiazem (MB7) and N-didemethyl clentiazem (MB8). The chemical structures of seven basic metabolites (MB9-15) were assigned as follows, deacetyl-N-didemethyl clentiazem (MB9), O-demethyl-N-didemethyl clentiazem (MB10), deacetyl-O-demethyl-N-didemethyl clentiazem (MB11), N-monodemethyl-2-hydroxy-methoxyphenyl clentiazem (MB12), deacetyl-2-hydroxy-methoxyphenyl clentiazem (MB13), deacetyl-N-monodemethyl-2-hydroxy-methoxyphenyl clentiazem (MB14) and deacetyl-N-didemethyl-2-hydroxy-methoxyphenyl clentiazem (MB15). Four acidic metabolites were identified as the synthetic compounds: (+)-(2S,3S)-3-(acetyloxy)-8-chloro-3,4-dihydro-2-(4-methoxyphenyl) -4-oxo-1, 5-benzothiazepin-5(2H)-acetic acid (MA1), deacetyl-MA1 (MA2), O-demethyl-MA1 (MA3) and deacetyl-O-demethyl-MA1 (MA4); and the two remaining acidic metabolites, MA5 and MA6, were presumed to be hydroxylated MA3 and MA4, respectively. Two neutral metabolites were identified as the synthetic compounds; (+)-(2S,3S)-3-(acetyloxy)-8-chloro-3,4-dihydro-2-(4-methoxyphenyl) -4-oxo-1, 5-benzothiazepin-5(2H)-acetonitrile (MN1) and deacetyl MN1 (MN2). Other two metabolites conjugated with glucuronic acid were found in bile and the structures were presumed to be 8-chloro-2,3-dihydro-3-hydroxy-5-(2-hydroxyethyl)-2-(4-hydroxyphenyl)-1, 5-benzothiazepin-4(5H)-one (MN3) and 2-methoxyphenyl MN3 (MN4). The glucuronide or sulfate of MA4 was also detected. These metabolites were formed by a number of pathways including deacetylation, deamination, N-demethylation, O-demethylation, aromatic hydroxylation and conjugation.

Disposition and metabolic fate of clentiazem in rats and dogs.

The plasma concentrations and time courses of radioactivity and unchanged drug, the excretion of radioactivity into urine and feces, and the proportion of metabolites in plasma and urine were studied after oral administration of [14C]clentiazem to male and female rats and dogs. Apparent sex-related differences were found in the disposition and metabolism of clentiazem in rats. The plasma levels of radioactivity and acidic metabolites were higher in males than in females. The plasma levels of unchanged drug, on the other hand, were about the same in both sexes. Higher conversion of clentiazem to its acidic metabolites in the liver of male rats and higher excretion of the acidic metabolites in the urine of female rats, presumably due to sex-related differences in cytochrome P-450 and renal clearance, respectively, seem to explain these differences in the disposition of clentiazem in male and female rats. No suggestion of a similar sex difference was found in dogs. The plasma concentrations and time courses of radioactivity and unchanged drug in male dogs were similar to those in female dogs, and the excretion of radioactivity in both sexes was also similar. The main plasma metabolite in male and female dogs was O-demethyl clentiazem (MB7). A species difference between rat and dog was suggested, since the major metabolic pathways were different and no sex difference was found in dogs.

Metabolism of diltiazem. I. Structures of new acidic and basic metabolites in rat, dog and man.

The metabolites of diltiazem in the urine of rats, dogs and man and rat bile were investigated. New metabolites including six acidic metabolites (A1-A6) and four basic metabolites (M9, MB, MC, MD) were isolated by high performance liquid chromatography and their structures were characterized by gas chromatography-mass spectrometry. Acidic metabolites A1, A2, A3, A4 and basic metabolite MD identified by comparing their properties with the synthetic compounds; (+)-(2S, 3S)-2-(4-methoxyphenyl)-3-acetoxy-4-oxo-2,3,4,5-tetrahydro-1,5- benzothiazepin-5-acetic acid (A1), 3-deacetyl-A1 (A2), O-demethyl-A1 (A3), O-demethyl-3-deacetyl-A1 (A4) and N-didemethyl-diltiazem (MD). All acidic metabolites have a CH2COOH group which may be formed by oxidative deamination of the CH2CH2N(CH3)2 group of diltiazem.

Metabolism of diltiazem. II. Metabolic profile in rat, dog and man.

The metabolism of diltiazem was studied in male rats and dogs after intravenous administration of 14C-diltiazem.HCl or in men after oral administration of a tablet of diltiazem.HCl. The main metabolites in rat urine, in decreasing order of content, were A4, M6, M4 and M5. The unchanged drug in the urine accounted for only 0.7% of the administered drug based on radioactivity. About 81% of biliary radioactivity in rat was due to water-soluble metabolites and the remainder was mostly acidic metabolites such as A4 and A6. In dog urine, the unchanged drug was most abundant (30.6% of the radioactivity in the 6-h urine), followed by A2, A1 and M2. The main metabolites of diltiazem in rat plasma were A2 and A4, while in dog plasma, the unchanged drug and A2 were found as main components. In human urine, M4, the unchanged drug, A2, MB, MD and M2 were the major components. Acidic metabolites, A1-A4, were found also in human plasma and A2 was the main metabolite found. These results indicated that the main metabolic pathway of diltiazem was an oxidative deamination which is extensive in the rat. Other metabolic pathways recognized in this study were oxidative demethylation, deacetylation, hydroxylation of the aromatic ring and conjugation. Although direct comparison may not be appropriate because of the different routes of administration, the metabolism of diltiazem in man appears to be more similar to that in the dog than that in the rat.

[Pharmacokinetic and cardiac efficacy of beta-acetyldigoxin and digitoxin in combination therapy with diltiazem]. / Pharmakokinetik und kardiale Wirksamkeit von beta-Acetyldigoxin und Digitoxin unter einer Kombinationstherapie mit Diltiazem.

The effect of diltiazem (D) on the pharmacokinetics and pharmacodynamics of beta-acetyldigoxin (AD; n = 12) and digitoxin (DGT; n = 10) was studied in 22 patients with cardiac insufficiency stages II-III by the New York Heart Association. Glycoside plasma concentration and renal excretion as well as electrocardiogram [heart rate, atrioventricular transconduction time (PQ), duration of electrical systole corrected for heart rate (QTc), mean amplitude of T-waves in leads V2 to V6 (TV2-6)] and systole time intervals [total electromechanical systole index (QS21), left ventricular ejection time index (LVETI), pre-ejection period index (PEPI), PEP/LVET ratio] were recorded repeatedly before and during co-administration of 180 mg/day D. In eight patients digoxin plasma levels increased continuously during additional D administration. After reaching a new steady state at 0.93 +/- 0.35 ng/ml digoxin concentrations were at an average 43% higher than before D administration (0.65 +/- 0.27 ng/ml) with a simultaneous increase in renal glycoside excretion. The other four patients showed neither changes in digoxin concentrations in plasma nor in renal glycoside excretion. Only half the patients treated with DGT and D revealed an increase in DGT plasma levels of 21.4%. Daily renal glycoside excretion was not altered by D administration. In accordance to the increasing AD plasma concentration, PQ-interval was prolonged and T-wave flattening was intensified, whereas the systolic time intervals after concomitant treatment of AD and D did not differ from those after AD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

High-performance liquid chromatographic determination of diltiazem and six of its metabolites in human urine.

The use of the calcium antagonist diltiazem (I) is increasing, particularly in treating unstable angina. This study describes a simple and specific high-performance liquid chromatographic method for the determination of I and six of its metabolites in urine. Diltiazem and its conjugated and unconjugated metabolites were assayed in the urine of patients treated with a dose of 120 mg po of diltiazem tid. Sensitivity of the method was 100 ng/mL for I and the metabolites desacetyldiltiazem (II), N-desmethyldesacetyldiltiazem (IV), O-desmethyldesacetyldiltiazem (V), O-desmethyl-N-desmethyldesacetyldiltiazem (VII), N-oxide desacetyldiltiazem (III), and O-desmethyl-N-oxide desacetyldiltiazem (VI). In the urine of patients, the extent of conjugation of six metabolites was greater than 80%.

Studies on the metabolism of diltiazem in man.

The human urinary metabolites of diltiazem were analyzed by thin-layer chromatography (TLC) and gas chromatography-mass spectrometry. Diltiazem was metabolized by deacetylation, N-demethylation, O-demethylation and conjugation. Metabolite MA, N- monodemethyl -diltiazem, was identified as a new major metabolite in human urine, and four metabolites were identified as deacetyl-diltiazem (M1), deacetyl-N- monodemethyl -diltiazem (M2), deacetyl-O-demethyl-diltiazem (M4), deacetyl-N,O-demethyl-diltiazem (M6) which were known as rat urinary metabolites. Metabolite M2, M4 and M6 were converted in part to glucuronides and/or sulfates. Unchanged diltiazem and metabolite MA were determined in human plasma and urine by TLC-densitometry. Diltiazem and metabolite MA excreted in 24-h urine were 44.4 and 48.5% of the total unconjugated form, respectively. The mean plasma level of metabolite MA was approximately one-third of diltiazem level. On the basis of these findings, a probable metabolic pathway of diltiazem in man is presented.