Chronopharmacology of verapamil in Stage I-II arterial hypertension

Aim. To compare the pharmacokinetics and pharmacodynamics of verapamil retard, regularly taken by patients  with Stage I-II arterial hypertension (AH).

 Material and methods. The effects of the administration time (morning vs. evening) on verapamil retard pharmacokinetics were investigated. This open, randomised, cross-over study included 14 patients with Stage I-II AH,  who were regularly administered verapamil retard for 3 weeks. Before the active therapy started, all antihypertensive medications were withdrawn, with an exception of short-acting agents (“wash-out” period). Two weeks later,  the patients were administered verapamil retard, according to the randomisation scheme, and were recommended  to take one tablet in the morning or evening, at the same time every day. The first administration was at the clinic,  under medical supervision. Three weeks later, the participants were hospitalised for pharmacokinetics assessment. Seven days after the end of the first treatment course, a second course started, with an inverted time of verapamil retard administration. Blood concentration of non-modified verapamil was measured by high-performance liquid chromatography with fluorescent detection.

Results. Significant differences in pharmacokinetics were observed for morning vs. evening verapamil administration. The respective maximal verapamil concentrations were 239,7±152,3 vs. 148,6±107,4 ng/ml (p<0,01), and respective half-life times were 12,50±3,48 vs. 22,57±15,24 hours (p<0,05). For other parameters, the difference was non-significant.

Conclusion. In Stage I-II AH patients, the morning administration of Isoptin SR resulted in accelerated increase of its plasma concentration. At the same time, the evening administration was associated with increased half-life time and higher “concentration-effect” correlation, which makes the latter variant more rational.

1. Lemmer B. Hypertension: do we need to consider the biological clock in drug dosing? Expert Rev Cardiovasc Ther 2007; 5(3): 370-5.

2. Lemmer B, Nold G, Behne S, Kaiser R. Chronopharmacokinetics and cardiovascular effects of nifedipine. Chronobiol Int 1991; 8: 485-94.

3. Mengren T, Binswanger B, Gruene S. Dynamics of drug compliance and 24-hour blood pressure control of once daily morning versus evening amlodipine [abstract]. J Hypertens 1992; 10(Suppl.4): S136.

4. Fagari R, Malacco E, Tettamanti F, et al. Evening vs. morning isradipine sustained release in essential hypertension: a double-blind study with 24 h ambulatory monitoring. Br J Clin Pharmacol 1993; 35: 51-4.

5. Portaluppi F, Vergnani L, Manfredini R, et al. Time-dependent effect of isradipine on the nocturnal hypertension of chronic renal failure. Am J Hypertens 1995; 8: 719-26.

6. Nold G, Strobel G, Lemmer B. Morning versus evening amlodipine treatment: effect on circadian blood pressure profile in essential hypertensive patients. Blood Press Monit 1998; 3: 17-25.

7. Hermida R, Calvo C, Ayala DE, et al. Administration timedependent effects of nifedipine GITS on ambulatory blood pressure in patients with essential hypertension [abstract]. Am J Hypertens 2005; 18(5 Pt 2): 63 A.

8. Sista S, Lai JC, Eradiri O, Albert KS. Pharmacokinetics of a novel diltiazem HCl extended-release formulation for evening administratin. J Clin Pharmacol 2003; 43: 1149-57.

9. Jespersеn CM, Frederiksen M, Fischer Hansen J, et al. Сircadian variation in the pharmacokinetics of verapamil. Eur J Clin Pharmacol 1989; 37: 613-5.

10. Fuenmayor NT, Faggin BM, Cubeddu LX. Comparative efficacy, safety and pharmacokinetics of verapamil SR vs.verapamil IR in hypertensive patiens. Drugs 1992; 44(Sappl.1): 1-11.

11. White WB, Anders RJ, Maclntyre JM, et al. Nocturnal dosing of of a novel delivery system of verapamil for systemic hapertension. Verapamil Study Group. Am J Cardiol 1995; 76: 375-80.

12. White WB, Mehrotra DV, Black HR, Fakouhi TD. Effects of controlled-oneset extended-releas verapamil on nocturnal blood pressure (dippers versus nondippers) COER-Verapamil Study Group. Am J Cardiol 1997; 80: 469-74.

13. Smith DH, Neutel JM, Weber MA. A new chronotherapeutic oral drug absorbtion system for verapamil optimizes blood pressure control in the morning. Am J Hypertens 2001; 14: 14-9.

14. Prisan LM, Devane JG, Butler J. A steady-state evalution of the bioavailability of chronotherapeutic oral drug absorption system verapamil PM after nighttime dosing versus immediate-acting verapamil dosed every eight hours. Am J Ther 2000; 7: 345-51.

15. Агафонов А.А., Пиотровский В.К. Программа M-IND оценки системных параметров фармакокинетики модельно-независимым методом статистических моментов. Хим Фарм ж 1991; 10: 16.

16. Gupta SK, Atkinson L, Tu T, Longstreth JA. Age and gender related changes in stereoselective pharmacokinetics and pharmacodynamics of verapamil and norverapamil. Br J Clin Pharmac 1995; 40(4): 325-31.

17. Кукес В.Г. Метаболизм лекарственных средств: клиникофармакологические аспекты. Москва 2004.

18. Jespersen CM, Frederiksen M, Hansen JF, et al. Circadian variation in the pharmacokinetics of verapamil. Eur J Clin Pharmacol 1989; 37(6): 613-5.

19. Hla KK, Latham AN, Henry JA. Influence of time of administration on verapamil pharmacokinetics. Clin Pharmacol Ther 1992; 51(4): 366-70.

20. Eldon MA, Battle MM, Voigtman RE, Colburn WA. Differences in oral verapamil absorption as a function of time of day. J Clin Pharmacol 1989; 29(11): 989-93.

21. Gupta SK, Yih BM, Atkinson L, Longstreth J. The effect of food, time of dosing, and body position on the pharmacokinetics and pharmacodynamics of verapamil and norverapamil. J Clin Pharmacol 1995; 35(11): 1083-93.

22. Dilger K, Eckhardt K, Hofmann U, et al. Chronopharmacology of intravenous and oral modified release verapamil. Br J Clin Pharmacol 1999; 47(4): 413-9.