Br. J. clin. Pharmac. (1979), 8, 163-167
PLASMA CONCENTRATIONS OF PROPRANOLOL AND 4-HYDROXYPROPRANOLOL DURING CHRONIC ORAL PROPRANOLOL THERAPY LORETTA WONG Department of Pharmacy Practice, College of Pharmacy
ROGER L. NATION & WIN L. CHIOU Clinical Pharmacokinetics Laboratory, Department of Pharmacy
P.K. MEHTA Section of Nephrology, University of Illinois at the Medical Center, Chicago, Illinois 60612, USA
1 The plasma levels of propranolol and 4-hydroxypropranolol have been measured in 17 hypertensive patients receiving chronic oral therapy with propranolol. 2 The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4hydroxypropranolol was from 2.1 to 36.0 ng/ml. 3 The mean ( ± s.d.) plasma concentration ratio of 4-hydroxypropranolol to propranolol was 0.130 (±0.055); however, a very wide range was observed with individual values ranging from 0.057 to 0.241. 4 A statistically significant correlation was observed between the plasma concentration of 4hydroxypropranolol and that of propranolol. 5 Propranolol and 4-hydroxypropranolol plasma concentrations were each significantly, but poorly, correlated with daily propranolol dose. 6 The clinical significance of the results has been discussed.
Introduction
Propranolol, a f-adrenergic receptor blocking drug, has found wide application in the control of disease states such as hypertension, angina pectoris and cardiac arrhythmias, but its use has also been suggested in other conditions. Since the discovery that propranolol forms at least one pharmacologically active metabolite (Fitzgerald & O'Donnell, 1971), 4-hydroxypropranolol, speculation has ensued about its therapeutic role. Fitzgerald & O'Donnell (1971) reported that propranolol and its 4-hydroxy metabolite were of similar potency, based on dosage, when tested for f-adrenoceptor blocking activity in animal models. Using 14C-labelled propranolol Paterson, Conolly, Dollery, Hayes & Cooper (1970) were able to detect 4-hydroxypropranolol in the blood of patients who received single doses of the parent drug orally, but not following intravenous administration. A similar observation has been made using radio-labelled material in the dog and monkey (Hayes & Cooper, 1971). In addition, in the dog, levels of 4-hydroxypropranolol comparable with those attained following oral administration of 0306-5251/79/080163-05 501.00
propranolol were observed after administration of the drug into the hepatic portal vein. Several theories have been tendered in an attempt to explain these findings (Paterson et al., 1970; Fitzgerald & O'Donnell, 1971; Hayes & Cooper, 1971). Further, it has been suggested, without corroborative plasma level data, that 4-hydroxypropranolol is present in plasma soon after a single oral dose of propranolol, but virtually absent during chronic oral therapy (Cleaveland & Shand, 1972). There is a paucity of information in the literature relating to the plasma concentration of 4-hydroxypropranolol achieved in patients who are receiving chronic oral therapy with propranolol. The considerable difficulties encountered in developing a chemical assay for this metabolite probably account in large measure for this situation. Only three brief reports appear to have been published on the topic (Walle, Morrison, Walle & Conradi, 1975a; Walle, Morrison, Walle & Conradi, 1975b; Walle, Conradi, Walle, Fagan & Gaffney, 1977). It is the purpose of the present paper to report the plasma concentrations of propranolol
© Macmillan Journals Ltd 1979
LORETTA WONG, ROGER L. NATION, P.K. MEHTA & WIN L. CHIOU
164
collected into a syringe by venipuncture, deposited in a glass tube containing 50 IU of heparin sodium, and sealed with a Teflon-lined screw cap. This procedure was used in order to avoid spurious assay results (Cotham & Shand, 1975). Blood samples were centrifuged, and plasma was harvested and stored in a frozen state until the time of analysis. The majority of the samples were analyzed within 2-14 days after collection, and the remainder within 1 month. The metabolite, 4-hydroxypropranolol, is stable under such conditions of storage (Garceau, Davis & Hasegawa, 1978). Each plasma sample was analyzed for propranolol and 4-hydroxypropranolol content in two replicates by a high pressure liquid chromatographic procedure (Nation, Peng & Chiou, 1978), and only the mean values are reported here.
and 4-hydroxypropranolol in a group of hypertensive patients who were receiving chronic oral propranolol therapy. Methods
The patient population was comprised of 17 (10 female, 7 male) ambulant hypertensive adults (Table 1). All patients had apparent normal hepatic function and 14 had no overt clinical signs of renal disease at the time of study; the remainder (patients 1, 3, and 17) either had clinical or laboratory indications of renal disease. 'The age range of the patients was 33-75 years and body weight range was 62-107 kg. Patients were prescribed propranolol at a dose recommended by their physician. Pregnant women, patients allergic to propranolol, patients with bronchial asthma, and patients with congestive heart failure not due to a tachyarrhythmia treatable with propranolol were excluded from the study. Length of oral therapy with propranolol ranged from 3 weeks to 3 years, and all patients had been on their present dosage regimen for at least 1 week (Table 1). Most patients were currently taking other drugs, including
Results The plasma concentrations of propranolol and 4hydroxypropranolol in the hypertensive patients are summarized in Table 2. The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4-hydroxypropranolol was from 2.1 to 36.0 ng/ml. In one subject (patient 10) measurable levels of the metabolite were not observed, and the concentration of propranolol was very low. The individual values of the ratio of the plasma concentration of the metabolite to that of the
antihypertensives. A single 5 ml venous blood sample was collected from each subject during a regular clinic visit, at least one hour after the time of the patient's previous propranolol dose (Table 1). Each blood sample was
Table 1 Details of the patients and their propranolol therapy. Duration
Patient 1 2 3 4
M
F F F
5
F
6 7 8 9 10
F F M
11
M
12 13 14 15 16 17 *
Sex
F F
F M M F M M
of pro-
present
pranolol therapy (years)
propranolol dose (weeks)
Propranolol daily dose (mg)
1.5 2.0 2.5 1.5 1.5 2.5
78 2 3 20 65 8 4 39 2 78 2 78 2 2 1 1 20
320 160 320 40 80 120 320 60 120 40 80 80 120 320 40 160 160
Age (years)
Weight (kg)
55 75 63 50 49 55 69 64 57 51 51 63 33 45 52 37
107 62 88 57 69 88 100 70 73
0.75 0.5 1.5
77 102 77 106 73 77
1.75 3.0 0.25 0.083 0.058 1.75
Unable to obtain information.
Time blood drawn after previous
Time on
propranolol Propranolol dose dose (h) (mg kg-' day-1) 1.49 5.15 0.46 1.40 1.74 3.63 0.60 1.71 0.55
1.04 1.18 4.14 0.38 2.20 2.07
1.75 3.17 3.00 3.83 1.25 1.67 2.25 3.17 2.75 6.58 2.75 2.50 5.67 1.83 5.00 1.33 3.17
PLASMA CONCENTRATIONS OF PROPRANOLOL AND 4-HYDROXYPROPRANOLOL 40
-
75 r-E 30 CL CoF tc
20
-
gXE 10 100
200
300
Propranolol in plasma (ng/ml) Figure 1 Relationship between plasma concentration of 4-hydroxypropranolol and that of propranolol in hypertensive patients receiving chronic oral propranolol therapy. (y=-0.0322+0.122x; r = 0.91 1; P < 0.005).
and propranolol plasma concentration, ratio and time the blood sample was drawn after the previous dose, ratio and the length oftime the patient had been receiving propranolol, and, finally, ratio and patient age (in all cases P> 0.3). However, propranolol plasma concentration and daily propranolol dose were significantly related, both when absolute dose (r = 0.739, P < 0.005) and dose adjusted on a body weight basis (r = 0.655, P < 0.05) were used. In a similar manner 4-hydroxypropranolol plasma concentration and daily propranolol dose were significantly correlated (absolute daily dose, r = 0.710, P
PLASMA CONCENTRATIONS OF PROPRANOLOL AND 4-HYDROXYPROPRANOLOL DURING CHRONIC ORAL PROPRANOLOL THERAPY LORETTA WONG Department of Pharmacy Practice, College of Pharmacy
ROGER L. NATION & WIN L. CHIOU Clinical Pharmacokinetics Laboratory, Department of Pharmacy
P.K. MEHTA Section of Nephrology, University of Illinois at the Medical Center, Chicago, Illinois 60612, USA
1 The plasma levels of propranolol and 4-hydroxypropranolol have been measured in 17 hypertensive patients receiving chronic oral therapy with propranolol. 2 The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4hydroxypropranolol was from 2.1 to 36.0 ng/ml. 3 The mean ( ± s.d.) plasma concentration ratio of 4-hydroxypropranolol to propranolol was 0.130 (±0.055); however, a very wide range was observed with individual values ranging from 0.057 to 0.241. 4 A statistically significant correlation was observed between the plasma concentration of 4hydroxypropranolol and that of propranolol. 5 Propranolol and 4-hydroxypropranolol plasma concentrations were each significantly, but poorly, correlated with daily propranolol dose. 6 The clinical significance of the results has been discussed.
Introduction
Propranolol, a f-adrenergic receptor blocking drug, has found wide application in the control of disease states such as hypertension, angina pectoris and cardiac arrhythmias, but its use has also been suggested in other conditions. Since the discovery that propranolol forms at least one pharmacologically active metabolite (Fitzgerald & O'Donnell, 1971), 4-hydroxypropranolol, speculation has ensued about its therapeutic role. Fitzgerald & O'Donnell (1971) reported that propranolol and its 4-hydroxy metabolite were of similar potency, based on dosage, when tested for f-adrenoceptor blocking activity in animal models. Using 14C-labelled propranolol Paterson, Conolly, Dollery, Hayes & Cooper (1970) were able to detect 4-hydroxypropranolol in the blood of patients who received single doses of the parent drug orally, but not following intravenous administration. A similar observation has been made using radio-labelled material in the dog and monkey (Hayes & Cooper, 1971). In addition, in the dog, levels of 4-hydroxypropranolol comparable with those attained following oral administration of 0306-5251/79/080163-05 501.00
propranolol were observed after administration of the drug into the hepatic portal vein. Several theories have been tendered in an attempt to explain these findings (Paterson et al., 1970; Fitzgerald & O'Donnell, 1971; Hayes & Cooper, 1971). Further, it has been suggested, without corroborative plasma level data, that 4-hydroxypropranolol is present in plasma soon after a single oral dose of propranolol, but virtually absent during chronic oral therapy (Cleaveland & Shand, 1972). There is a paucity of information in the literature relating to the plasma concentration of 4-hydroxypropranolol achieved in patients who are receiving chronic oral therapy with propranolol. The considerable difficulties encountered in developing a chemical assay for this metabolite probably account in large measure for this situation. Only three brief reports appear to have been published on the topic (Walle, Morrison, Walle & Conradi, 1975a; Walle, Morrison, Walle & Conradi, 1975b; Walle, Conradi, Walle, Fagan & Gaffney, 1977). It is the purpose of the present paper to report the plasma concentrations of propranolol
© Macmillan Journals Ltd 1979
LORETTA WONG, ROGER L. NATION, P.K. MEHTA & WIN L. CHIOU
164
collected into a syringe by venipuncture, deposited in a glass tube containing 50 IU of heparin sodium, and sealed with a Teflon-lined screw cap. This procedure was used in order to avoid spurious assay results (Cotham & Shand, 1975). Blood samples were centrifuged, and plasma was harvested and stored in a frozen state until the time of analysis. The majority of the samples were analyzed within 2-14 days after collection, and the remainder within 1 month. The metabolite, 4-hydroxypropranolol, is stable under such conditions of storage (Garceau, Davis & Hasegawa, 1978). Each plasma sample was analyzed for propranolol and 4-hydroxypropranolol content in two replicates by a high pressure liquid chromatographic procedure (Nation, Peng & Chiou, 1978), and only the mean values are reported here.
and 4-hydroxypropranolol in a group of hypertensive patients who were receiving chronic oral propranolol therapy. Methods
The patient population was comprised of 17 (10 female, 7 male) ambulant hypertensive adults (Table 1). All patients had apparent normal hepatic function and 14 had no overt clinical signs of renal disease at the time of study; the remainder (patients 1, 3, and 17) either had clinical or laboratory indications of renal disease. 'The age range of the patients was 33-75 years and body weight range was 62-107 kg. Patients were prescribed propranolol at a dose recommended by their physician. Pregnant women, patients allergic to propranolol, patients with bronchial asthma, and patients with congestive heart failure not due to a tachyarrhythmia treatable with propranolol were excluded from the study. Length of oral therapy with propranolol ranged from 3 weeks to 3 years, and all patients had been on their present dosage regimen for at least 1 week (Table 1). Most patients were currently taking other drugs, including
Results The plasma concentrations of propranolol and 4hydroxypropranolol in the hypertensive patients are summarized in Table 2. The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4-hydroxypropranolol was from 2.1 to 36.0 ng/ml. In one subject (patient 10) measurable levels of the metabolite were not observed, and the concentration of propranolol was very low. The individual values of the ratio of the plasma concentration of the metabolite to that of the
antihypertensives. A single 5 ml venous blood sample was collected from each subject during a regular clinic visit, at least one hour after the time of the patient's previous propranolol dose (Table 1). Each blood sample was
Table 1 Details of the patients and their propranolol therapy. Duration
Patient 1 2 3 4
M
F F F
5
F
6 7 8 9 10
F F M
11
M
12 13 14 15 16 17 *
Sex
F F
F M M F M M
of pro-
present
pranolol therapy (years)
propranolol dose (weeks)
Propranolol daily dose (mg)
1.5 2.0 2.5 1.5 1.5 2.5
78 2 3 20 65 8 4 39 2 78 2 78 2 2 1 1 20
320 160 320 40 80 120 320 60 120 40 80 80 120 320 40 160 160
Age (years)
Weight (kg)
55 75 63 50 49 55 69 64 57 51 51 63 33 45 52 37
107 62 88 57 69 88 100 70 73
0.75 0.5 1.5
77 102 77 106 73 77
1.75 3.0 0.25 0.083 0.058 1.75
Unable to obtain information.
Time blood drawn after previous
Time on
propranolol Propranolol dose dose (h) (mg kg-' day-1) 1.49 5.15 0.46 1.40 1.74 3.63 0.60 1.71 0.55
1.04 1.18 4.14 0.38 2.20 2.07
1.75 3.17 3.00 3.83 1.25 1.67 2.25 3.17 2.75 6.58 2.75 2.50 5.67 1.83 5.00 1.33 3.17
PLASMA CONCENTRATIONS OF PROPRANOLOL AND 4-HYDROXYPROPRANOLOL 40
-
75 r-E 30 CL CoF tc
20
-
gXE 10 100
200
300
Propranolol in plasma (ng/ml) Figure 1 Relationship between plasma concentration of 4-hydroxypropranolol and that of propranolol in hypertensive patients receiving chronic oral propranolol therapy. (y=-0.0322+0.122x; r = 0.91 1; P < 0.005).
and propranolol plasma concentration, ratio and time the blood sample was drawn after the previous dose, ratio and the length oftime the patient had been receiving propranolol, and, finally, ratio and patient age (in all cases P> 0.3). However, propranolol plasma concentration and daily propranolol dose were significantly related, both when absolute dose (r = 0.739, P < 0.005) and dose adjusted on a body weight basis (r = 0.655, P < 0.05) were used. In a similar manner 4-hydroxypropranolol plasma concentration and daily propranolol dose were significantly correlated (absolute daily dose, r = 0.710, P
