Jul 20, 1981 - Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) ... prazosin followed first-order kinetics with a linear correlation ...
Prazosin kinetics in hypertension Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) and after increasing multiple doses (0.5 to 5 mg three times daily) in eight patients with hypertension. After intravenous administration the kinetics could be described by a linear two-compartment open model. Terminal halfLlife (t1/20) was about 3 hr and apparent volume of distribution (Vdp) about 0.6 Ilkg. After oral doses bioavailability ranged between 55% and 82%. Since total plasma clearance was low (0.14 1/kg x hr) incomplete bioavailability was the result of incomplete absorption rather than of first-pass liver metabolism. The estimated extraction ratio was about 14%. Renal clearance was negligible; only 1% to 2% of the dose was recovered unchanged in urine. Binding to plasma proteins to both albumin and aracid glycoprotein was substantial (97%), with albumin being most important. Increasing multiple doses showed that prazosin followed first-order kinetics with a linear correlation between dose and steady-state plasma concentration (P < 0.001). There were substantial variations in plasma concentrations between patients and there were also day-to-day variations in concentration within the same patient.
Anders Grahnen, M.Pharm., Peter Seideman, M.D., Bjorn Lindstriim, Ph.D., Kjell Haglund, M.D., and Christer von Bahr, M.D. Uppsala, Huddinge, and Stockholm, Sweden Department of Drugs, National Board of Health and Welfare, Uppsala, Departments of Clinical Pharmacology and Medicine, Huddinge Hospital, Huddinge, and Karolinska Institutet, Stockholm
Prazosin is reported to reduce peripheral vascular resistance by blocking vascular aradrenergic receptors , 4 but the clinical kinetics of the drug have not been sufficiently characterized. Up to now, kinetic studies have used only single doses in healthy subjects" 6, 11, 23, 26 and hypertensive patients.7 There are only a few preliminary studies on the relationship between
Supported by grants from The Loo and Hans Osterman fund, the Swedish National Association against Chest and Heart Diseases and the Swedish Medical Research Council (04X-03902). Received for publication Feb. 20, 1981.
Accepted for publication July 20, 1981. Reprint requests to: Anders Grahnen, Department of Drugs, National Board of Health and Welfare, Box 607, S-751 25, Uppsala, Sweden.
maintenance doses and plasma concentrations in hypertensive patients elucidating possible dose-dependent kinetics.10' 15' 19 The methods used have been poorly defined since only single plasma samples have been examined and time for sampling has been arbitrary. We therefore studied the kinetics and effects of prazosin during continuous treatment of hypertensive patients over a dosage range. To get some insight into the relationships between absorption, liver extraction, and oral bioavailability, single oral and intravenous doses of the drug were also given. In this paper we describe prazosin kinetics. The relationships between its hypotensive effects and kinetics are reported in another article (see p. 447.).
0009-9236/81/100439+08$00.80/0 C) 1981 The C. V. Mosby Co.
439
440
Clin. Pharmacol, Ther.
Grahnen et al.
October 1981
(ngiml) 50 HA
MF
BG
ER
25
10
5
II
I
I
Ii
t A.
2
4
10B.
6
8
1.0 D.
4
6
8
10
Time(hr)
Fig. 1. Prazosin plasma concentrations (ng/ml) after single 0.5-mg intravenous (0 doses in four patients.
( )
Materials and methods
Patients. Our subjects were eight untreated patients (four men and four women) with essential hypertension (World Health Organization stage I or II). Secondary hypertension was excluded by routine procedures. If the diastolic blood pressure exceeded 105 mm Hg on three occasions, the patient was included in the study. Two subjects had left ventricular hypertrophy (diagnosed by ECG). All had normal serum creatinine values and renograms. All patients were without subjective symptoms and none had any evidence of any concurrent disease. None had received antihypertensive therapy during the preceding year. Age ranged from 28 to 54 yr and weight from 65 to 110 kg. Design of study. The subjects were outpatients throughout the study except for 8 to 12-hr observation periods (6 to 10 times). Patients were allowed to become accustomed to the automatic blood pressure recorder used (Arteriosonde8) the day before the drug therapy began. The next day they took a single 0.5-mg placebo tablet. Blood pressure, pulse rate, and blood samples for analysis of plasma concentrations were recorded before dose and at 0.5, 1, 2, 4, 6, 8, 10, and 12 hr. With 1-wk intervals the same protocol was repeated for a 0.5-mg
*) and oral
tablet and an intravenous injection of 0.5 mg (in four patients) of prazosin (Peripress). Blood samples were taken and recordings were made before and at 5, 10, 20, and 30 min and at 1, 2, 3, 5, 8, 10, and 12 hr after the injection. Prazosin, 0.5 mg three times daily, was then started. After 2 wk patients were admitted to the hospital ward where blood pressure, pulse rate, and prazosin plasma concentrations were measured before the morning dose and at 2, 4, 6, and 8 hr after. On the 2 days preceding the observation period, plasma concentrations and other drug effects were measured during a short outpatient visit to control day-to-day variation. The prazosin dose was then increased according to the therapeutic response and after another 2 wk an identical procedure was repeated with doses up to 5 mg three times daily. The patients were always fasted in the morning and no food was allowed until the 2-hr blood sample had been drawn. Sampling procedures. Blood samples for analysis of prazosin and protein binding were drawn into heparinized Venoject tubes. Samples were immediately centrifuged and the plasma frozen at 200 until analyzed. Urine was collected for 36 hr during the single-dose experiments.
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Prazosin kinetics in hypertension
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Table I. Kinetics of prazosin, 0.5 mg, after intravenous injection Patient Parameter
a (hr') t1/2a (hr)
(hr-1) (hr)
B. G.
E. R.
6.3 0.11
4.6 0.15
0.26
0.31 2.3
2.7 3.89
t1/2/3
(hr-') K21 (hr-') Kel (hr-') K12
VI (//kg) Vdfi' (//kg)
AUC (ng/ml x hr) Cltot (1/kg X hr) Cifree (//kg x hr) ERest (%)
H. A.
M. F.
1.9
6.3 0.11 0.29 2.4 3.61 1.64 1.07
0.37 0.19 3.7 0.39
2.26
1.96
1.79
1.45
0.84 0.12 0.52 61.2 0.117 4.3
0.77 0.12 0.62 38.4 0.186 6.5
0.25
11
17
fe (%)
1.0
(//kg x hr) C111 free (1/kg x hr)
0.001 0.043
C111
0.21
0.46 58.3 0.086 1.9
39.5 0.186 7.1 16
11
2.4 0.005 0.156
0.14 0.68
1.0 0.001
2.1
0.019
0.004 0.149
Mean
-±
SD
4.8 ± 2.1 0.19 -± 0.12 0.26 ± 0.05 2.8 ± 0.6 2.54 ±- 1.60 1.71 ± 0.22 0.73 ± 0.35 0.15 -± 0.04 0.57 ±- 0.10 49.4 -± 12.0 0.144 ± 0.05 5.0 -± 2.4 13.8 ± 3.2 1.6 ± 0.7 0.003 ± 0.002 0.092 ± 0.071
K = rate constant for transfer of drug from compartment one to two; K2, = rate constant for transfer of drug from compartment two to one; Kel = elimination rate constant from central compartment; V, = volume of central compartment. For definitions of other parameters, see kinetic analysis section of text.
Table II. Kinetic data for prazosin after a single oral dose of 0.5 mg Patient B. E. M. B. J. R. K. B. L. H. A. E. R. B. G. M. E.
± SD
Sex
Weight (kg)
AUC (nglml x hr)
tams
t1/20
(nglml)
(hr)
(hr)
98
4.9
14.5
