Advertisement

Pharmacokinetics and tissue distribution of clevidipine and its metabolite in dogs and rats

  • Ying Zhou (周 莹)
  • Xiao-meng He (何晓梦)
  • Hu-qun Li (李虎群)
  • Yang Ni (倪 扬)
  • Ming-zhen Xu (许明珍)
  • Hui Chen (谌 辉)Email author
  • Wei-yong Li (黎维勇)Email author
Article

Summary

The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The pharmacokinetics and biodistribution of its primary metabolite H152/81 were also evaluated. Dogs received intravenous infusion of clevidipine at a dose rate of 17 μg/(kg·min), and rats were given intravenous administration of clevidipine at a dose of 5 mg/kg. Dog plasma and rat tissues were collected and assayed by HPLC-MS/MS. It was found that plasma clevidipine quickly reached the steady state concentration. The terminal half-life was short (16.8 min), pointing out a rapid elimination after the end of the infusion. The total clearance was 5 mL/(min·kg). In comparison, plasma concentration of H152/81 was increased more slowly and was significantly higher than that of clevidipine. After intravenous administration, clevidipine was distributed rapidly into all tissues examined, with the highest concentrations found in the brain, heart and liver. Maximal concentrations of clevidipine were found in most tissues at 10 min post-dosing. However, the proportion of clevidipine distributed in all tissues was quite small (0.042‰) compared to the total administration dose. It was suggested that clevidipine was mainly distributed in blood and it transformed to inactive metabolite rapidly.

Key words

pharmacokinetics tissue distribution clevidipine metabolite 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Peacock WF, Angeles JE, Soto KM, et al. Parenteral clevidipine for the acute control of blood pressure in the critically ill patient: a review. Ther Clin Risk Manag, 2009, 5(3):627–634PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Ericsson H, Bredberg U, Eriksson U, et al. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology, 2000, 92(4):993–1001PubMedCrossRefGoogle Scholar
  3. 3.
    Feldstein C. Management of hypertensive crises. Am J Ther, 2007, 14(2), 135–139PubMedCrossRefGoogle Scholar
  4. 4.
    Varon, J, Marik, PE. Clinical review: the management of hypertensive crises. Crit Care, 2003, 7(5):374–384PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Levy JH. The ideal agent for perioperative hypertension and potential cytoprotective effects. Acta Anaesthesiol Scand Suppl, 1993, 37(99):20–25CrossRefGoogle Scholar
  6. 6.
    Brooks TW, Finch CK, Lobo BL, et al. Blood pressure management in acute hypertensive emergency. Am J Health Syst Pharm, 2007, 64(24):2579–2582PubMedCrossRefGoogle Scholar
  7. 7.
    Cheung AT. Exploring an optimum intra/postoperative management strategy for acute hypertension in the cardiac surgery patient. J Card Surg, 2006, 21(1):8–14CrossRefGoogle Scholar
  8. 8.
    Smith WB, Marbury TC, Komjathy SF, et al. Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension. Eur J Clin Pharmacol, 2012, 68(10):1385–1394PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Levy JH, Mancao MY, Gitter R, et al. Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine assessing its preoperative antihypertensive effect in cardiac surgery-1. Anaesth Analg, 2007, 5(4):918–925CrossRefGoogle Scholar
  10. 10.
    Singla N, Warltier DC, Gandhi SD, et al. Treatment of acute postoperative hypertension in cardiac surgery patients: an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized, doubleblind, placebo-controlled trial. Anesth Analg, 2008, 107(1):59–67PubMedCrossRefGoogle Scholar
  11. 11.
    Nordlander M, Sjoquist PO, Ericsson H, et al. Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultra short-acting calcium antagonist for rapid blood pressure control. Cardiovasc Drug Rev, 2004, 22(3):227–250PubMedCrossRefGoogle Scholar
  12. 12.
    Ericsson H, Tholander B, Regirdh CG. In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashortacting calcium antagonist metabolised by esterases, in different animal species and man. Eur J Pharm Sci, 1999, 8(1):29–37PubMedCrossRefGoogle Scholar
  13. 13.
    Ericsson H, Fakt C, Hoglund L, et al. Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion. Eur J Clin Pharmacol, 1991, 55(1): 61–67CrossRefGoogle Scholar
  14. 14.
    Zhang JG, Dehal SS, Ho T, et al. Human cytochrome P450 induction and inhibition potential of clevidipine and its primary metabolite H152/81. Drug Metab Dispos, 2006, 34(5): 734–737PubMedCrossRefGoogle Scholar
  15. 15.
    Zhou Y, Li HQ, He XM, et al. Simultaneous determination of clevidipine and its primary metabolite in dog plasma by liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic study. J Pharm Biomed Anal, 2014, 100:294–299PubMedCrossRefGoogle Scholar
  16. 16.
    Bailey JM, Lu W, Levy JH, et al. Clevidipine in adult cardiac surgical patients: a dose-finding study. Anesthesiology, 2002, 96(5):1086–1094PubMedCrossRefGoogle Scholar

Copyright information

© Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ying Zhou (周 莹)
    • 1
  • Xiao-meng He (何晓梦)
    • 1
  • Hu-qun Li (李虎群)
    • 1
  • Yang Ni (倪 扬)
    • 1
  • Ming-zhen Xu (许明珍)
    • 1
  • Hui Chen (谌 辉)
    • 1
    Email author
  • Wei-yong Li (黎维勇)
    • 1
    Email author
  1. 1.Institute of Clinic Pharmacy, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations