Summary. The duration and extent of cardiac beta- blockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy vol- unteers.
European Journal of Clinical Pharmacology © Springer-Verlag1987
Eur J Clin Pharmacol (1987) 32:315-318
Propranolol Pharmaeokinetics and Pharmaeodynamies After Single Doses and at Steady-State* R. L. Lalonde, J. A. Pieper, R.J. Straka, M. B. Bottorff, and D. M. Mirvis Departments of Clinical Pharmacy and Medicine, University of Tennessee, Memphis, Tennessee, USA
Summary. The duration and extent of cardiac betablockade and their relationship to propranolol pharmacokinetics were assessed in nine healthy volunteers. Each subject received 160 mg of regular propranolol (R), 160 mg of sustained-release propranolol (SR) and no drug (control), both as single doses and once daily for 7 days. After single doses and at steady-state, both products caused a decrease in exercise heart rate for at least 24 h, compared to control. The time course of effect was similar to the time course of serum propranolol concentration. The oral clearance of propranolol decreased from single doses to steadystate for both R and SR; however, the difference achieved statistical significance only for R. These changes were reflected in mean accumulation ratios (AUC steady-state 0-24 h / A U C single dose 0-infinity) of 1.49 and 1.68 for R and SR, respectively. The pharmacokinetic data are consistent with a decrease in intrinsic hepatic clearance of propranolol, leading to an increase in bioavailability at steady-state. Despite a two-fold difference in the bioavailability of R and SIL there was no difference in the area under the effect-time curve at steadystate.
Key words: propranolol; pharmacodynamics, pharmacokinetics, beta-blockade, sustained-release propranolol
Propranolol has been shown to accumulate upon chronic dosing to an extent greater than that expected based on single dose pharmacokinetics (Wood et * Presented in part at the III World Conference on Clinical Pharmacology and Therapeutics, Stockholm, Sweden, July 1986
al. 1978). Also, Silber et al. (1983) have demonstrated a 56% reduction in propranolol's intrinsic clearance measured at steady-state as the dose was increased from 40 to 320 mg per day. This change in intrinsic clearance coupled with metabolite urinary excretion data, suggests the elimination of propranolol is nonlinear over this dosage range. Using these data, Wagner (1985) has shown that propranolol input rate profoundly affects its bioavailability. The consequences of propranolol's nonlinear pharmacokinetics and its implications upon cardiac betablockade have yet to be fully investigated. The purpose of this study is to investigate the effects of acute and chronic once daily oral administration of regular or sustained-release propranolol and the relationship between the pharmacokinetics, and the duration and extent of cardiac beta-blockade.
Methods Nine healthy male volunteers ranging in age from 23 to 39 years (mean age 27 years) and ranging in weight from 66 to 82 kg (mean weight 75 kg), participated in the study. The subjects had no evidence of previous or current cardiac, respiratory, renal or hepatic dysfunction. All were nonsmokers and abstained from taking caffeine containing products, other drugs and alcohol for the duration of the study. The study was a randomized cross-over comparison of three regimens. During Phase I (single dose phase), each subject received one sustained-release propranolol (SR) 160 mg capsule (Inderal LA, Ayerst Laboratories Inc., New York, NY), regular propranolol (R) 160 mg (two 80 mg Inderal tablets) and no drug at all (control period). The doses were administered at approximately 8:00 a.m. and the subjects fasted for 8 h before and
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4 h after drug administration. At least 7 days passed before proceeding to the next regimen. After completion of Phase I, all subjects entered a multiple dose study (Phase II) using the same randomized cross-over design. During Phase II, each drug was taken once daily for 7 days with at least one drugfree week between each regimen. On the last day of each regimen during Phase II and on the test days of Phase I, subjects underwent repeated treadmill exercise tests. Each test was performed on a motor driven treadmill at 6 mph, 10% grade for 2.5 min, immediately before drug administration (time 0 for control period) and then at 2, 4, 8, 12, 24, 32 and 48 h. Arterial blood pressure and an electrocardiogram were recorded immediately after each exercise and heart rate (HR) was determined over 15 consecutive R-R intervals. Percentage reduction in HR was calculated as the difference between post exercise control HR and that measured after propranolol ingestion divided by the control HR then multiplied by 100. After the single doses in Phase I and the last doses in Phase II, blood was collected by direct venipuncture at 0, I, 2, 4, 6, 8, 12, 24, 32 and 48 h. No heparin was used in the sample collection. The serum was separated and frozen at - 2 0 °C until analysis. Serum concentrations of propranolol and 4-hydroxypropranolol were measured by HPLC with fluorescence detection (Lo et al. 1982). Intra- and inter-day coefficients of variation for propranolol and its metabolite ranged from 1.5% to 10.5%, over the range of concentrations observed in this study, with a limit of sensitivity of 1 ng/ml. Standard noncompartmental equations were used to calculate the area under the serum concentration-time curve
(AUC), terminal elimination rate constant (k) and apparent oral clearance (CL). AUC was calculated to infinity after single doses and over 24 h at steadystate. The kinetic parameters were compared by Friedman's analysis of variance and the heart rate data were compared by parametric ANOVA. Post-hoc tests were done using nonparametric multiple comparison and Newman-Keuls tests, respectively (Conover 1980). Paired comparisons were done using the Wilcoxon paired-sample test.
Results
The mean serum propranolol concentration-time curves are shown in Fig. 1 and the individual pharmacokinetic parameters are summarized in Table 1. With each product, the AUC over one dosing interval at steady-state was larger than the AUC after a single dose. The above AUC increase was evident in 8 of 9 subjects with R (p < 0.05). A similar average AUC increase was evident with SR; however, because it occurred in only 6 of 9 subjects, the difference did not achieve statistical significance. The average AUC increases were 49% and 68% for R and SR, respectively (p >0.05 between products). The bioavailability of SR relative to R did not change significantly between single doses and at steadystate (0.55+_0.30 vs 0.52+0.11, p >0.05). The k values were consistently smaller with SR compared to R (p < 0.05), probably because of continued absorption with SR. However, there was no significant change in k values between single dose and steadystate. After administration of R, the molar ratios of
Table 1. Propranolol pharmacokinetic and pharmacodynamic parameters for the regular (R) and sustained-release (SR) products Subjects
AUC (ng.h.m1-1)
k (h -1)
Single dose
Steady-state
Single dose
CL (ml.min -1 .kg -a)
AUC Effect (% reduction in HR)
Steady-state
Single dose
Steady-state
Steady-state
R
SR
R
SR
R
68.0 33.9 102.7 30.9 34.5 26.6 35.3 36.6 49.5
125.6 t19.6 129.7 58.3 77.7 23.7 124.8 192.4 63.1
24.4 25.6 64.5 30.2 27.5 15.6 26.8 36.8 34.6
55.1 49.8 132.7 71.3 35.9 32.3 61.8 73.9 56.0
479 467 402 456 551 473 432 576 265
392 402 192 356 538 437 581 422 590
101.7 b (50.6)
31,8c (13.7)
63.2b (32.4)
456a (90)
434a (125)
R
SR
R
SR
R
SR
R
1 2 3 4 5 6 7 8 9
544 990 317 1048 1074 1296 1004 1105 717
294 280 251 555 477 1455 284 210 563
1516 1307 504 1071 1346 2204 1324 1099 1026
671 673 245 454 1032 1065 574 547 634
0.205 0.132 0.190 0.160 0.185 0.126 0.213 0.231 0.152
0.069 0.107 0.085 0.065 0.058 0.088 0.073 0.042 0.069
0.165 0.140 0.178 0.149 0.172 0.149 0.219 0.181 0.205
Mean +SD
900 a (310)
486 b (388)
1267 c (455)
655 b (259)
SR
0.063 0.121 0.025 0.063 0.078 0.054 0.064 0.122 0.092
0.177 a 0.073 b 0.173 a 0.076 b (0.037) (0.019) (0.026) (0.032)
For each parameter, means with different letters differ at p < 0.05
46.5 a 24.5)
SR
R. L. Lalonde et al. : Propranolol at Steady-State
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