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. 1987 Aug;91(4):735–745. doi: 10.1111/j.1476-5381.1987.tb11271.x

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

S J Downing 1, D Edwards 1, M Hollingsworth 1
PMCID: PMC1853582  PMID: 3664075

Abstract

1 The kinetics of diltiazem were investigated in ovariectomized (ovx) non-pregnant and intact late pregnant anaesthetized rats following a bolus i.v. injection (2 mg kg-1) and during a 180 min i.v. infusion (50 micrograms kg-1 min-1 and 100 micrograms kg-1 min-1). 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 k12 - 0.46 +/- 0.10 min-1; k21 - 0.09 +/- 0.01 min-1; kel - 0.13 +/- 0.03 min-1; elimination clearance - 3.2 +/- 0.3 ml min-1; distribution t1/2 (t1/2) - 1.4 +/- 0.3 min; elimination t1/2 (t1/2 beta) - 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(area) - 1004 +/- 184 ml; kel - 0.54 +/- 0.16 min-1 and elimination clearance - 14.8 +/- 2.3 ml min-1. 3 Measurement of serum diltiazem concentrations during infusion yielded the following parameters in non-pregnant ovx rats: V(ss)--79 +/- 10 ml; rate constants k12 - 1.02 +/- 0.21 min-1; k21 - 0.03 +/- 0.01 min-1; kel - 0.39 +/- 0.06 min-1; elimination clearance - 7.8 +/- 1.2 ml min-1. In pregnant rats a marked increase was observed in kel - 1.25 +/- 0.38 min-1 and elimination clearance - 36.4 +/- 13.8 ml min-1. 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 IC50 values of 0.5 microgram ml-1 for inhibition of uterine contractions, 0.7 microgram ml-1 for reduction in blood pressure and 1.2 micrograms ml-1 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.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

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  1. Abel M. H., Hollingsworth M. Comparison of nifedipine and diltiazem with salbutamol for prevention of preterm delivery in the ovariectomized, oestrogen-treated late pregnant rat. J Reprod Fertil. 1986 Jul;77(2):559–568. doi: 10.1530/jrf.0.0770559. [DOI] [PubMed] [Google Scholar]
  2. Abel M. H., Hollingsworth M. The effects of long-term infusion of salbutamol, diltiazem and nifedipine on uterine contractions in the ovariectomized, post-partum rat. Br J Pharmacol. 1986 Jul;88(3):577–584. doi: 10.1111/j.1476-5381.1986.tb10238.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Abel M. H., Hollingsworth M. The potencies and selectivities of four calcium antagonists as inhibitors of uterine contractions in the rat in vivo. Br J Pharmacol. 1985 May;85(1):263–269. doi: 10.1111/j.1476-5381.1985.tb08855.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Atherton J. C., Dark J. M., Garland H. O., Morgan M. R., Pidgeon J., Soni S. Changes in water and electrolyte balance, plasma volume and composition during pregnancy in the rat. J Physiol. 1982 Sep;330:81–93. doi: 10.1113/jphysiol.1982.sp014330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bolton T. B. Mechanisms of action of transmitters and other substances on smooth muscle. Physiol Rev. 1979 Jul;59(3):606–718. doi: 10.1152/physrev.1979.59.3.606. [DOI] [PubMed] [Google Scholar]
  6. EDMAN K. A., SCHILD H. O. The need for calcium in the contractile responses induced by acetylcholine and potassium in the rat uterus. J Physiol. 1962 May;161:424–441. doi: 10.1113/jphysiol.1962.sp006897. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Edwards D., Good D. M., Granger S. E., Hollingsworth M., Robson A., Small R. C., Weston A. H. The spasmogenic action of oxytocin in the rat uterus--comparison with other agonists. Br J Pharmacol. 1986 Aug;88(4):899–908. doi: 10.1111/j.1476-5381.1986.tb16264.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Granger S. E., Hollingsworth M., Weston A. H. A comparison of several calcium antagonists on uterine, vascular and cardiac muscles from the rat. Br J Pharmacol. 1985 May;85(1):255–262. doi: 10.1111/j.1476-5381.1985.tb08854.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Granger S. E., Hollingsworth M., Weston A. H. Effects of calcium entry blockers on tension development and calcium influx in rat uterus. Br J Pharmacol. 1986 Jan;87(1):147–156. doi: 10.1111/j.1476-5381.1986.tb10166.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hall D. G., Fahim M. S., Famim Z., Der R., Dement G. The effect of progesterone on hepatic metabolism in animals and humans. J Reprod Med. 1971 Mar;6(3):116–124. [PubMed] [Google Scholar]
  11. Meshi T., Sugihara J., Sato Y. Metabolic fate of d-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride (CRD-401). Chem Pharm Bull (Tokyo) 1971 Aug;19(8):1546–1556. doi: 10.1248/cpb.19.1546. [DOI] [PubMed] [Google Scholar]
  12. Otway S., Robinson D. S. The significance of changes in tissue clearing-factor lipase activity in relation to the lipaemia of pregnancy. Biochem J. 1968 Feb;106(3):677–682. doi: 10.1042/bj1060677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Verghese C., Smith M. S., Aanonsen L., Pritchett E. L., Shand D. G. High-performance liquid chromatographic analysis of diltiazem and its metabolite in plasma. J Chromatogr. 1983 Jan 14;272(1):149–155. doi: 10.1016/s0378-4347(00)86111-3. [DOI] [PubMed] [Google Scholar]
  14. Wiens R. E., Runser D. J., Lacz J. P., Dimmitt D. C. Quantitation of diltiazem and desacetyldiltiazem in dog plasma by high-performance liquid chromatography. J Pharm Sci. 1984 May;73(5):688–689. doi: 10.1002/jps.2600730525. [DOI] [PubMed] [Google Scholar]
  15. Yabana H., Nagao T., Sato M. Cardiovascular effects of the metabolites of diltiazem in dogs. J Cardiovasc Pharmacol. 1985 Jan-Feb;7(1):152–157. doi: 10.1097/00005344-198501000-00025. [DOI] [PubMed] [Google Scholar]

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