Leuer to the Editors
Br. J. clin. Pharmac. (1990), 30
499
Nicardipine does not influence the pharmacokinetics and pharmacodynamics of atenolol We recently reported that nicardipine increases the bioavailability of propranolol, probably by impaired hepatic 'first-pass' clearance (Schoors et al., 1990). Propranolol is an example of a lipophilic 3-adrenoceptor blocker, with a high hepatic extraction ratio (Cruikshank & Prichard, 1988). We found it of interest to study whether co-administration of nicardipine could influence the pharmacokinetics or the pharmacodynamics of atenolol, a hydrophylic 1adrenoceptor blocker, which undergoes little metabolism in the liver and is eliminated almost completely unchanged in the urine. As dihydropyridines, such as nicardipine, may enhance splanchnic and renal blood flow, both the resorption and the renal excretion of atenolol could theoretically be expected to be altered by nicardipine. Six healthy male volunteers (aged 23-27 years) and six healthy female volunteers (aged 23-41 years) were investigated, following an identical protocol as described previously (Schoors et al.,. 1990). In brief, subjects were studied on two separate occasions, at 1 week intervals. They were allocated to receive either atenolol alone (100 mg, orally) or atenolol (100 mg) in combination with nicardipine (30 mg, orally) at 09.00 h, following a randomized crossover design. Blood pressure was taken before and 2, 4 and 8 h after drug ingestion. Blood samples, for determination of the plasma concentrations of atenolol, were obtained prior to the morning dose and 30, 60, 120, 180, 240, 360 and 480 min following administration of the dose. The assay of atenolol in plasma was performed using h.p.l.c. as analytical technique in combination with solid phase extraction for the sample treatment (Musch & Massart, 1988). The area under the curve (AUC) was determined using the trapezoidal method. The maximum concentration (Cma.) and the time to peak plasma concentration (tm.) are the observed values. Statistical analysis was performed by analysis of variance and the Wilcoxon paired-sample test as appropriate. Differences were considered statistically significant if a two-tailed P < 0.05. All data are presented as means ± s.e. mean.
80or
k
1-
E
600
c. 0ZD-a
X 0 400 E X.X ' 200 A.o0 o
L
II
I
0
2
4
I,
I
6
I
8;h
Time (h) Figure 1 Plasma atenolol concentration-time course after oral administration of atenolol 100 mg with (e) and without (o) nicardipine 30 mg. Mean data (s.e. mean), n = 12.
Co-administration of nicardipine did not significantly change the Cma and tm. of atenolol nor the area under the curve during the first 8 h (417.2 ± 24.6 ng mi' min without nicardipine vs 448.7 ± 29.9 ng mi71 min with nicardipine; NS). The two plasma concentration-time curves are indeed superimposable (Figure 1). Both systolic and diastolic blood pressure decreased 2, 4 and 8 h after drug intake, reaching a maximal effect 4 h after dosing (decrease in systolic blood pressure from 113.8 ± 3.6 to 93.6 ± 2.9 mm Hg and in diastolic blood presure from 70.3 ± 2.7 to 61.7 ± 2.1 mm Hg with atenolol alone; decrease in systolic blood pressure from 112.3 ± 4.1 to 94.8 ± 3.7 mmHg and in diastolic blood pressure from 71.5 ± 2.7 to 58.2 ± 1.8 mm Hg with atenolol in combination with nicardipine). Heart rate decreased after drug intake and still remained lower after 8 h (from 73.3 ± 2.2 beats mini1 to 63.2 ± 2.4 beats min71 with atenolol alone and from 73.7 ± 2.4 beats min71 to 64.7 ± 2.1 beats min-1 with atenolol in combination with nicardipine). There was no significant difference between atenolol alone and its combination with nicardipine, regarding the response of blood pressure or heart rate. The data from this study indicate that nicardipine does not change the pharmacokinetics or pharmacodynamics of atenolol. Similarly, the pharmacokinetics of atenolol was also not altered by nifedipine or diltiazem
Correspondence: Dr D. F. Schoors,. Department of Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium
500
Letter to the Editors
(Gangji et al., 1984; Kendall et al., 1984; Rosenkranz et al., 1986; Tateishi et al., 1989). The effect of nicardipine on the bioavailability of propranolol (Schoors et al., 1990) should therefore not be extrapolated to all, and certainly not to hydrophylic 3-adrenoceptor blockers. D.F.S. is a Research Assistant of the National Fund for Scientific Research (NFWO), Belgium.
Br. J. clin. Pharnac. (1990), 30 I. VERCRUYSSE1, D. F. SCHOORS2, G. MUSCH1, D. L. MASSART1 & A. G.
DUPONT2 iDepartment of Pharmaceutical Analysis and 2Department of Pharmacology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
Received 19 February 1990, accepted 9 April 1990
References Cruickshank, J. M. & Prichard, B. N. C. (1988). Betablockers in clinical practice, 1st ed., pp. 177-275. London: Churchill Livingstone. Gangji, D., Juvent, M., Niset, G., Wathieu, M., Degreve, M., Bellens, R., Poortmans, J., Degre, S., Fitzsimons, T. J. & Herchuelz, A. (1984). Study of the influence of nifedipine on the pharmacokinetics and pharmacodynamics of propranolol, metoprolol and atenolol. Br. J. clin. Pharmac., 17, 29S-35S. Kendall, M. J., Jack, D. B., Laugher, S. J., Lobo, J. & Rolf Smith, S. (1984). Lack of a pharmacokinetic interaction between nifedipine and the 1-adrenoceptor blockers metoprolol and atenolol. Br. J. clin. Pharmac., 18, 331-335. Musch, G. & Massart, D. L. (1988). Isolation of basic drugs from plasma using solid-phase extraction
with a cyanopropyl-bonded phase. J. Chromatogr., 432., 209-222. Rosenkranz, B., Ledermann, H. & Frolich, J. C. (1986). Interaction between nifedipine and atenolol: pharmacokinetics and pharmacodynamics in normotensive volunteers. J. cardiovasc. Pharmac., 8, 943-949. Schoors, D. F., Vercruysse, I., Musch, G., Massart, D. L. & Dupont, A. G. (1990). Influence of nicardipine on the pharmacokinetics and pharmacodynamics of propranolol in healthy volunteers. Br. J. clin. Pharmac., 29, 497-501. Tateishi, T., Nakashima, H., Shitou, T., Kumagai, Y., Ohashi, K., Hosoda, S. & Ebihara, A. (1989). Effect of diltiazem on the pharmacokinetics of propranolol, metoprolol and atenolol. Eur. J. clin. Pharmac., 36, 67-70.
Br. J. clin. Pharmac. (1990), 30
499
Nicardipine does not influence the pharmacokinetics and pharmacodynamics of atenolol We recently reported that nicardipine increases the bioavailability of propranolol, probably by impaired hepatic 'first-pass' clearance (Schoors et al., 1990). Propranolol is an example of a lipophilic 3-adrenoceptor blocker, with a high hepatic extraction ratio (Cruikshank & Prichard, 1988). We found it of interest to study whether co-administration of nicardipine could influence the pharmacokinetics or the pharmacodynamics of atenolol, a hydrophylic 1adrenoceptor blocker, which undergoes little metabolism in the liver and is eliminated almost completely unchanged in the urine. As dihydropyridines, such as nicardipine, may enhance splanchnic and renal blood flow, both the resorption and the renal excretion of atenolol could theoretically be expected to be altered by nicardipine. Six healthy male volunteers (aged 23-27 years) and six healthy female volunteers (aged 23-41 years) were investigated, following an identical protocol as described previously (Schoors et al.,. 1990). In brief, subjects were studied on two separate occasions, at 1 week intervals. They were allocated to receive either atenolol alone (100 mg, orally) or atenolol (100 mg) in combination with nicardipine (30 mg, orally) at 09.00 h, following a randomized crossover design. Blood pressure was taken before and 2, 4 and 8 h after drug ingestion. Blood samples, for determination of the plasma concentrations of atenolol, were obtained prior to the morning dose and 30, 60, 120, 180, 240, 360 and 480 min following administration of the dose. The assay of atenolol in plasma was performed using h.p.l.c. as analytical technique in combination with solid phase extraction for the sample treatment (Musch & Massart, 1988). The area under the curve (AUC) was determined using the trapezoidal method. The maximum concentration (Cma.) and the time to peak plasma concentration (tm.) are the observed values. Statistical analysis was performed by analysis of variance and the Wilcoxon paired-sample test as appropriate. Differences were considered statistically significant if a two-tailed P < 0.05. All data are presented as means ± s.e. mean.
80or
k
1-
E
600
c. 0ZD-a
X 0 400 E X.X ' 200 A.o0 o
L
II
I
0
2
4
I,
I
6
I
8;h
Time (h) Figure 1 Plasma atenolol concentration-time course after oral administration of atenolol 100 mg with (e) and without (o) nicardipine 30 mg. Mean data (s.e. mean), n = 12.
Co-administration of nicardipine did not significantly change the Cma and tm. of atenolol nor the area under the curve during the first 8 h (417.2 ± 24.6 ng mi' min without nicardipine vs 448.7 ± 29.9 ng mi71 min with nicardipine; NS). The two plasma concentration-time curves are indeed superimposable (Figure 1). Both systolic and diastolic blood pressure decreased 2, 4 and 8 h after drug intake, reaching a maximal effect 4 h after dosing (decrease in systolic blood pressure from 113.8 ± 3.6 to 93.6 ± 2.9 mm Hg and in diastolic blood presure from 70.3 ± 2.7 to 61.7 ± 2.1 mm Hg with atenolol alone; decrease in systolic blood pressure from 112.3 ± 4.1 to 94.8 ± 3.7 mmHg and in diastolic blood pressure from 71.5 ± 2.7 to 58.2 ± 1.8 mm Hg with atenolol in combination with nicardipine). Heart rate decreased after drug intake and still remained lower after 8 h (from 73.3 ± 2.2 beats mini1 to 63.2 ± 2.4 beats min71 with atenolol alone and from 73.7 ± 2.4 beats min71 to 64.7 ± 2.1 beats min-1 with atenolol in combination with nicardipine). There was no significant difference between atenolol alone and its combination with nicardipine, regarding the response of blood pressure or heart rate. The data from this study indicate that nicardipine does not change the pharmacokinetics or pharmacodynamics of atenolol. Similarly, the pharmacokinetics of atenolol was also not altered by nifedipine or diltiazem
Correspondence: Dr D. F. Schoors,. Department of Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090 Brussels, Belgium
500
Letter to the Editors
(Gangji et al., 1984; Kendall et al., 1984; Rosenkranz et al., 1986; Tateishi et al., 1989). The effect of nicardipine on the bioavailability of propranolol (Schoors et al., 1990) should therefore not be extrapolated to all, and certainly not to hydrophylic 3-adrenoceptor blockers. D.F.S. is a Research Assistant of the National Fund for Scientific Research (NFWO), Belgium.
Br. J. clin. Pharnac. (1990), 30 I. VERCRUYSSE1, D. F. SCHOORS2, G. MUSCH1, D. L. MASSART1 & A. G.
DUPONT2 iDepartment of Pharmaceutical Analysis and 2Department of Pharmacology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
Received 19 February 1990, accepted 9 April 1990
References Cruickshank, J. M. & Prichard, B. N. C. (1988). Betablockers in clinical practice, 1st ed., pp. 177-275. London: Churchill Livingstone. Gangji, D., Juvent, M., Niset, G., Wathieu, M., Degreve, M., Bellens, R., Poortmans, J., Degre, S., Fitzsimons, T. J. & Herchuelz, A. (1984). Study of the influence of nifedipine on the pharmacokinetics and pharmacodynamics of propranolol, metoprolol and atenolol. Br. J. clin. Pharmac., 17, 29S-35S. Kendall, M. J., Jack, D. B., Laugher, S. J., Lobo, J. & Rolf Smith, S. (1984). Lack of a pharmacokinetic interaction between nifedipine and the 1-adrenoceptor blockers metoprolol and atenolol. Br. J. clin. Pharmac., 18, 331-335. Musch, G. & Massart, D. L. (1988). Isolation of basic drugs from plasma using solid-phase extraction
with a cyanopropyl-bonded phase. J. Chromatogr., 432., 209-222. Rosenkranz, B., Ledermann, H. & Frolich, J. C. (1986). Interaction between nifedipine and atenolol: pharmacokinetics and pharmacodynamics in normotensive volunteers. J. cardiovasc. Pharmac., 8, 943-949. Schoors, D. F., Vercruysse, I., Musch, G., Massart, D. L. & Dupont, A. G. (1990). Influence of nicardipine on the pharmacokinetics and pharmacodynamics of propranolol in healthy volunteers. Br. J. clin. Pharmac., 29, 497-501. Tateishi, T., Nakashima, H., Shitou, T., Kumagai, Y., Ohashi, K., Hosoda, S. & Ebihara, A. (1989). Effect of diltiazem on the pharmacokinetics of propranolol, metoprolol and atenolol. Eur. J. clin. Pharmac., 36, 67-70.
