Summary
Deacetyl N-monodesmethyl diltiazem (M2) is a major metabolite of the widely used calcium antagonist diltiazem (DTZ). In order to study the pharmacokinetic and haemodynamic effects of this metabolite, M2 was administered as a single 5 mg/kg dose intravenously (i.v.) to New Zealand white rabbits (n=5) via a marginal ear vein. Blood samples, blood pressure (SBP and DBP), and heart rate (HR) recordings were obtained from each rabbit up to 8 h, and urine samples for 48 h post-dose. Plasma concentrations of M2 were determined by HPLC. The results showed that there were no identifiable basic metabolites which could be quantified and characterized in the plasma. The apparent terminal t1/2 and AUC were 2.8±0.7 h and 2000±290 ng.h/ml, respectively. The Cl and Clr of M2 were 38±4.8 ml/min/kg and 0.57±0.23 ml/min/kg, respectively. M2 significantly decreased blood pressure (SBP and DBP) for up to 2 h post-dose (P <0.05), but had no significant effect on the heart rate (P > 0.05). The Emax and EC50 as estimated by the inhibitory sigmoidal Emax model were 15±7% and 450±46 ng/ml, respectively, for SBP; 15±20% and 430±120 ng/ml for DBP.
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References
Medical Letter (1993): Drugs for hypertension. Med. Lett., 35, 55–60.
Medical Letter 1994): Drugs for stable angina pectoris. Med. Lett., 36, 111–114.
Weir, M. (1995): Diltiazem: ten years of clinical experience in the treatment of hypertension. J. Clin. Pharmacol., 35, 220–232.
Yeung P.K.F., Montague T.J., Tsui B., McGregor C. (1989): High performance liquid chromatographic assay of diltiazem and six of its metabolites in plasma: application to a pharmacokinetic study in healthy volunteers. J. Pharm. Sci., 78, 592–597.
Caille G., Boucher S., Spenard J. et al. (1991): Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses. Eur. J. Drug Metab. Pharmacokinet., 16, 75–80.
Hussain M., Tam Y., Gray M., Coutts R. (1994): Mechanisms of time-dependent kinetics of diltiazem in the isolated perfused rat liver. Drug Metab. Dispos., 22, 36–42.
Yeung P.K.F., Buckley S., Hung O. et al. (1996): Steady-state plasma concentrations of diltiazem and its metabolites in patients and helathy volunteers. Ther. Drug Monit., 18, 40–45.
LeBoeuf E., Grech-Belanger O. (1987): Deacetylation of diltiazem by rat liver. Drug Metab. Dispos., 15, 122–126.
Pichard L., Gillet G., Fabre I. et al. (1990): Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metab. Dispos., 18, 711–719.
Yeung P.K.F., Buckley S., Buckley S., Cameron R., Feng J., Jordan J. (1996): Effect of phenobarbital pre-treatment on the pharmacokinetics and metabolism of diltiazem in rats. Drug Metab. Drug Interact., 13, 29–39.
Yabana H., Nagao T., Sato M. (1985): Cardiovascular effects of the metabolites of diltiazem in dogs. J. Cardiovasc. Pharmacol., 7, 152–157.
Kiyomoto A., Sasaki Y., Odawara A., Morita T. (1983): Inhibition of platelet aggregation by diltiazem. Circ. Res., 52 (Suppl. 1), 115–119.
Yeung P.K.F., Mosher S.J., MacRae D.A., Klassen G.A. (1991): Effect of diltiazem and its metabolites on the uptake of adenosine in blood: an in-vitro investigation. J. Pharm. Pharmacol., 43, 685–689.
Li R., Farmer P.S., Xie M. et al. (1992): Synthesis, characterization and calcium antagonistic activity of diltiazem metabolites. J. Med. Chem., 35, 3246–3253.
Caille G., Dube L.M., Theoret Y., Varin F., Mousseau N. (1989): Stability study of diltiazem and two of its metabolites using a high-performance liquid chromatographic method. Biopharm. Drug Dispos., 10, 107–114.
McLean A.M., Cefali E.A., Roden J.S., Gonzalez M.A., Bialer M. (1991): Stability of diltiazem in different biological fluids. Biopharm. Drug Dispos., 12, 327–334.
Yeung P.K.F., Mosher S.J., Klassen G.A., McGilveray I.J. (1991): Stability of diltiazem and its metabolites in plasma during storage. Ther. Drug Monit., 13, 369–374.
Gibaldi M., Perrier D. (1982): Pharmacokinetics. Drugs and the Pharmaceutical Sciences. Swarbrick (ed). New York, USA: Marcel Dekker.
Fleishaker J.C., Phillips J.P., Smith T.C., Smith R.B. (1989): Multiple-dose pharmacokinetics and pharmacodynamics of adinazolam in elderly subjects. Pharm. Res., 6, 379–386.
Yeung P.K.F., Mosher S.J., Pollak P.T. (1991): Pharmacokinetics and metabolism of diltiazem in rabbits after a single intravenous or single oral administration. Eur. J. Drug Metab. Pharmacokinet., 16, 69–74.
Holford N., Sheiner L. (1981): Pharmacokinetic and pharmacodynamic modeling in vivo. CRC Crit. Rev. Bioeng., July, 273–321.
Gabrielsson J., Weiner D. (1994): Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts and Applications. Stockholm, Sweden: Swedish Pharmaceutical Press.
Yeung P.K.F., Feng J., Buckley S. (1997): Pharmacokinetics and haemodynamic effect of deacetyl diltiazem (M1) in rabbits after a single intravenous administration. Biopharm. Drug Dispos., In press.
Sugawara Y., Ohashi M., Nakamura S. et al. (1988): Metabolism of diltiazem. 1. Structures of new acidic and basic metabolites in rats, dog and man. J. Pharmacobio-Dyn., 11, 211–223.
Halbrugge T., Friedgen B., Ludwig J., Graefe K-H. (1993): Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit. Naunyn-Schmiedeberg’s Arch Pharmacol., 347, 162–170.
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Yeung, P.K.F., Feng, J.D.Z. & Buckley, S.J. Pharmacokinetics and hypotensive effect of deacetyl N-monodesmethyl diltiazem (M2) in rabbits after a single intravenous administration. European Journal of Drug Metabolism and Pharmacokinetics 23, 27–31 (1998). https://doi.org/10.1007/BF03189823
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DOI: https://doi.org/10.1007/BF03189823