Br. J. clin. Pharmac. (1979), 7, 569-574
PHARMACOKINETICS, PHARMACOLOGY OF ATENOLOL AND EFFECT OF RENAL DISEASE S.H. WAN, R.T. KODA & R.F. MARONDE The Schools of Pharmacy and Medicine, Section of Clinical Pharmacology, University of Southern California and the Los Angeles County/USC Medical Center, Los Angeles, California
I The pharmacokinetics of intravenous and oral atenolol (50 mg) in six healthy volunteers was studied. Plasma, saliva and urine were collected up to 24 h after each dose. 2 There was no significant difference in atenolol half-life when administered by the two routes. Bioavailability of the orally administered atenolol was 50%. 3 Atenolol levels in saliva required about 2 h to reach equilibrium with plasma drug levels. 4 A comparison between the pharmacokinetics and pharmacology of atenolol was made in twelve healthy subjects. 5 Dose-independent pharmacokinetics were observed. Reductions in resting heart rate and arterial blood pressure were proportional to either the logarithm of dose or area under the plasma concentration time curve or cumulative urinary atenolol excretion. 6 Plasma elimination half-life in five subjects with renal failure was prolonged.
Introduction Atenolol [4-(2'-hydroxy-3'-isopropylaminopropoxy) phenyl acetamide] is a P-adrenoceptor blocking agent with antihypertensive properties (Amery, Billiet, Joossens, Meekers, Reybrouk & Van Mieghem, 1973; Graham, Littlejohns, Prichard, Scales & Southorn, 1973; Hansson, Aberg, Jameson, Karlberg & Malmerona, 1973). Its pharmacological properties have been compared in animals with those of propranolol and practolol ( Barrett, Carter, Fitzgerald, Hill & Le Count, 1973; Hainsworth, Karim & Stoker, 1974; Harry, Knapp & Linden, 1973). The fiadrenoceptor blocking effects of orally administered atenolol have been compared with the effects of similar doses of propranolol in human volunteers (Harry, Knapp & Lindin, 1974). The effects of atenolol indicated a preferential blockade of cardiac fiadrenoceptors with potency similar to propranolol. It does not possess membrane stabilizing properties and intrinsic sympathomimetic activity. The limited pharmacokinetic studies that have been performed in man indicate a half-life of about 6 h following a 100 mg oral dose with 45% of the oral dose excreted in urine by 48 h (Brown, Carruthers, Johnston, Kelly McAinsh, McDevitt & Shanks, 1976; Conway, Fitzgerald, McAinsh, Rowlands & Simpson, 1976; McAinsh, 1977). The present study was performed to further elucidate the pharmacokinetic behavior of atenolol in healthy subjects and in subjects with renal disease; and to assess any effects that single oral doses of 0306-5251/060569-06 $01.00
atenolol might have on resting heart rate and blood pressure of healthy volunteers.
Methods
Study 1: Comparison of intravenous and oral administration Six healthy male volunteers, ages 22-27 years, weighing between 64.5 to 79.9 kg (mean weight 72.9 kg) participated in this study. Each subject underwent a complete examination including a screening history, physical examination, 12 lead electrocardiogram and laboratory tests on blood and urine. Subjects were excluded if there was a history or evidence of diabetes or asthma, haematological, cardiovascular, gastrointestinal, hepatic or renal disease. Subjects with significant physical or laboratory abnormality and recent medication were also excluded. Qualified subjects were then hospitalized for the duration of the study. Following an overnight fast, and approximately 45 min before drug administration, subjects drank 500 ml water to ensure adequate urine output. Each subject received, on two separate occasions at least 72 h apart, 50mg atenolol as a rapid intravenous injection and orally as a 50 mg tablet (supplied by ICI, USA) with 120 ml water. A standard house diet was served 2-3 h after dosing. Blood, mixed saliva and all c Macmillan Joumals Ltd
1979
570
S.H. WAN, R.T. KODA & R.F. MARONDE
urine was collected at specified intervals up to 24 h. To avoid repeated venipuncture, blood was withdrawn from an indwelling catheter, inserted into a superficial vein in the forearm, into heparinized tubes.
Study 2: Comparison of 25, 50 and 100 mg oral doses Twelve healthy male volunteers, ages 21 to 36 years and weighing between 64.5 to 87.6 kg (mean weight 68.6 kg) participated in this study. The screening procedure for subject selection was similar to that described in Study 1. Each subject received on three separate occasions, tablets containing 25, 50 or 100 mg atenolol together with 100 ml water following an overnight fast. The 25 mg dose was given in the first dosing period followed by 50mg in the second dosing period and 100 mg in the third dosing period. The interval between each dose was a miniimum of 72 h. Subjects were allowed moderate activity except during blood pressure measurements and when blood samples were withdrawn. At specified intervals, resting heart rate and supine blood pressure were measured after 10 min rest in the recumbent position. Standing blood pressure was recorded immediately after assuming the standing position. Blood was obtained pre-drug and at specified times after drug administration up to 24 h. All urine was collected at 24 h intervals for a period of 72 h. Plasma and urine was frozen until analysis.
Study 3: Effect of renal disease Six hypertensive subjects, four males and two females with impaired renal function participated in this study. Subjects were between 35 and 64 years of age and
Table 1
weighed between 69.9 and 99.9 kg (mean weight 76.5 kg). Creatinine clearance was between 15 and 42 ml/min. The protocol for drug administration was similar to that described in Study 1. A single 50 mg oral dose was administered to the patient in addition to other medication listed in Table 1. Blood was obtained at appropriate intervals up to 48 h and all urine was collected at 12 and 24 h postdrug for determination of atenolol concentration. Subjects in all three studies were informed of the nature of the study, the duration and type of hazards to be expected and written consent obtained. Atenolol concentration in saliva, plasma and urine was measured by a gas chromatographic technique (Malbica & Monson, 1975; Wan, Maronde & Matin, 1978).
Results
Comparison ofintravenous and oral administration Mean (s.e. mean) plasma and saliva atenolol concentration following intravenous and oral administration is shown in Figures 1 and 2. The plasma concentration data following intravenous administration reflected a three compartment open model of the following form: C(t) = Pe"t + Aeat + Be-t
Where C(t) is plasma atenolol concentration at time t; P, A, B are coefficients and ,r, a, ,B are hybrid rate constants. Mean plasma atenolol concentrations were fitted to the above model using a least squares iterative method (14) with a weighting factor of 1/(concentra-
Clinical and pharmacokinetic data for subjects with renal failure
% of dose
Subject
Sex
1
M
2
F
3 4 5 6
F M M M
Medication
a-methyidopa, flurazepam, prochlorperazine, acetaminophen, aluminium hydroxide gel, frusemide, clonidine guanethidine, clonidine, hydralazine, frusemide, digoxin guanethidine, hydrochlorothiazide, allopurinol a-methyidopa, hydrochlorothiazide, insulin a-methyidopa, frusemide clonidine, hydrochlorothiazide, hydralazine, insulin
*
Not available
Haff-life (h) NA
28.0 21.4 13.72 10.98 14.03
excreted in 24 h 7.72 33.7
28.4
29.1 35.1 39.5
Creatinine clearance
(ml/min) 2.06 19.80
13.25 45.65 18.17 19.25
EFFECT OF RENAL DISEASE ON ATENOLOL PHARMACOKINETICS
571
5
E 0,
1
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0
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8
12
16
20
24
Time (h) 0.01
i
L L-
I
0
4
8
12
16
I
20
I
24
Figure 2 Mean (s.e. mean) plasma (-) and saliva (0) concentration of atenolol following oral administration of 50 mg atenolol in healthy volunteers, (n=6).
Time (h)
Figure 1 Mean (s.e. mean) plasma (S) and saliva (0) concentration of atenolol following intravenous administration of 50 mg atenolol in healthy volunteers, (n = 6).
tion)2 and the continuous line in Figure 1 represents the computer drawn curve which is given by: C (ng/ml) = 1615e-5.10 h-'t +
150oe-0881 h-'t
+
8OOe0- 130 h-'t
The close proximity of the observed data to the fitted curve indicates a good fit for the proposed model and the mean terminal half-life of 5.33 h is in reasonable agreement with the mean half-life of 6.06 h reported in previous studies (Brown et al., 1976). Peak plasma atenolol levels were reached at about 3 h following oral administration of drug. The expected triphasic decline was masked by the absorption phase and only a biphasic drug concentration decline was observed. The mean terminal half-life of 4.88 h after oral administration was not significantly different from the half-life of 5.33 h after intravenous dosing (P> 0.05). Both urinary excretion data and area under the plasma concentration-time curves (AUC) indicate a bioavailability of about 50% for the oral dose. At 24 h
the percent of the dose excreted in urine was 102.0 (s.d. 17.1) and 50.2 (s.d. 16.3) for the intravenously and orally administered drug respectively, while the AUC was 7888 (s.d. 1976) and 4113 (s.d. 1563) ng h ml-'. AUC was calculated by the trapezoidal method. Saliva atenolol concentration required about 2 h to reach equilibrium with plasma drug levels and an equilibrium saliva/plasma concentration ratio of 0.47 (s.d. 0.23) and 0.41 (s.d. 0.29) were reached during the intravenous and oral studies. Once equilibrated, saliva concentration decline paralleled that of plasma and half-lives determined from saliva atenolol concentrations were 5.25 h and 3.60 h for the intravenous and oral studies respectively. The latter value is subject to considerable error since the estimate was based on only two data points. Because salivary drug levels are much lower than plasma levels and do not reflect the latter during the lengthy equilibration phase, salivary drug measurements are probably not useful for pharmacokinetic studies of this drug, but may still be useful for monitoring steady-state drug levels during chronic dosing and for assessing patient compliance. According to previous studies (Matin, Wan & Karam, 1974; Wan, Matin & Azarnoff, 1978) the equilibrium saliva/plasma drug concentration ratio is a function of drug protein binding in saliva and plasma, pKa of drug and pH difference between saliva and plasma if passive diffusion is the primary mechanism of transfer of drug between plasma and saliva. Atenolol is a
S.H. WAN, R.T. KODA & R.F. MARONDE
572
1000r 5001
\
E l100 C
50
0 C
0
-
co
50
100 0
5
1 cn(..ma)pasacnetaino
Fro
0
4
8
12
16
20
24
Time (h)
Figure 3 Mean (s.e. mean) plasma concentration of atenolol following oral administration of 25 (0), 50 (A) and 100 (U) mg atenolol in healthy volunteers, (n= 12).
relatively hydrophilic compound. The low
saliva/plasma ratio for atenolol observed in the present study suggests that partition coefficient could also be a factor in determining this ratio. Table 2
Comparison of25, 50 and 100 mg oral doses Mean (s.e. mean) plasma concentration of atenolol at doses of 25, 50 and 100 mg is presented in Figure 3. Data for the 100 mg dose represents only eleven subjects since one individual who had exhibited bradycardia at the 50 mg pre-dose period and during the 25 and 50 mg dose periods was not administered the 100 mg dose. Estimates of the pharmacokinetic parameters for this study are presented in Table 2. Good estimates of the various pharmacokinetic parameters at the 50 and 100 mg dose were obtained. In the case of the 25 mg dose, measurable atenolol levels were not present for many subjects at 0.5 h and beyond 8 h and the data for this study were not subjected to non-linear regression analysis. Peak plasma concentrations were proportional to dose at the 25 and 50 mg dose level but were low for the 100 mg dose indicating smaller percentage absorption with the latter dose which is confirmed by cumulative excretion in urine of 36.6% versus 48.0% and 40.7% for the 25 and 50 mg doses. Renal clearance was obtained by dividing the total amount of drug excreted in urine by AUC. Both the AUC and renal clearance do not indicate any trend related to dose. Formulation differences between the 25, 50 and 100 mg doses are a possible explanation for the lower absorption with the 100 mg dose. In Table 3, a comparison between doses is made for relative reductions in mean resting heart rate and arterial blood pressures at the time of peak plasma concentration. In designing the study protocol, resting heart rate measurements were primarily intended as a monitor of drug safety and possible cardiotoxicity rather than degree of fi-adrenoceptor blockade which is better assessed by maxiimum exercise tachycardia (Amery, DePlaen, Lijnen, McAinsh & Reybrouk, 1977; Matin et al., 1974; Shanks, Carruthers, Kelly & McDevitt, 1977). At the time of peak plasma levels, both the resting heart rate and blood pressure were decreased. The percent reductions were essentially
Mean pharmacokinetic parameters of subjects administered 25, 50 and 100 mg atenolol
Dose (mg) Parameter
Elimination T, (h) AUC*(tg h ml-') 0-24 h 0-co h Renal clearance (I/h) 0-24 h 0-co h Percent of dose excreted in urine 0-24 h 0-72 h I
Area under plasma concentration time curve
25
50
100
0.840 0.856
7.23 2.41 2.64
6.12 3.95 4.23 8.50 8.64
12.7 14.0 42.7 48.0
7.58 7.70 36.5 40.7
33.6 36.6
EFFECT OF RENAL DISEASE ON ATENOLOL PHARMACOKINETICS
573
8r a-
a) co
4C
CID
10 loIt
6
0)
._
-t 01)
m C
4
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c; 0)
-C
0'
25
I
I
50
100
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
2.64
0.856
AUC (gAg h ml-1)
Dose (mg)
I
4.23
20.4 36.6
5.5
Amount excreted (mg)
Figure 4 Relationship between percent reductions in heart rate (A), supine arterial pressure (0), standing arterial pressure (0) and the logarithm of dose, AUC and cumulative drug excretion, (n= 12).
Pharmacokinetics in renal disease 1.0
Mean (s.e. mean) plasma atenolol concentrations for subjects with moderate to severe renal failure are given in Figure 5 and some pertinent clinical and pharmacokinetic data are presented in Table 1. Figure 5 represents data from only five subjects since subject 1 subsequently underwent dialysis and the data for this subject are not included. As expected, since renal excretion is the major route of elimination, a marked prolongation in terminal half-life was observed in this group of patients, with a half-life range of 10.13-28.0 h which is in accord with previously published observations (Sassard, Pozer, McAinsh, Legheard & Zech, 1977). At the same time 24 h urinary excretion of atenolol dropped to a mean of 28.9 (s.d. 4.56) percent of the dose.
0.5
vI
1
E
oE ° o.1
a)4-0 M
E 0.05 X
0.01 ________.____.____.____.____.___ 0
10
20
30
40
50
Time (h) 1-1 .
Figure 5 Mean (s.e. mean) plasma atenolol centration in subjects with renal failure, (n = 5).
con-
proportional to the logarithm of dose (Figure 4). A linear relationship was also obtained between the relative reduction of heart rate and blood pressure and the logarithm of AUC and cumulative excretion of drug in urine. In this case it is probably more accurate to use AUC and cumulative drug excretion since the extent of absorption appears to be dose related. AUC and cumulative drug excretion reflect the amount of drug absorbed whereas dose does not.
Table 3 Percent reductions in mean heart rate and blood pressure 2 h after the oral administration of 25, 50 and 100 mg of atenolol
Atenolol (mg) 100 50 % reduction % reduction % reduction 25
Heart rate 4.6 (beats/min) Supine blood pressure 2.8 Systolic 0.0 Diastolic 0.9 Arterial Standing blood pressure 8.4 Systolic 0.9 Diastolic 3.3 Arterial
7.2
10.9
8.0 4.9 6.0
10.4 6.9 8.0
9.3 5.0 6.4
11.7 6.1 8.0
574
S.H. WAN, R.T. KODA & R.F. MARONDE
References AMERY, A., DePLAEN, J., LIJNEN, P., McAINSH, J. &
REYBROUK, T. (1977). Relationship between blood level of atenolol & pharmacologic effect. Clin. Pharmac. Ther., 21, 691-699. AMERY, A., BILLIET, L., JOOSSENS, J.V., MEEKERS, J., REYBROUK, T. & VAN MIEGHEM, W. (1973).
Preliminary report on the hemodynamic response of hypertensive patients treated with a P-blocker (ICI 66082). Acta Clinica Belgica, 29, 358-363. BARRETT, A.M., CARTER, J., FITZGERALD, J.D., HILL, R. & LE COUNT, D. (1973). A new type of cardioselective
adrenoceptive blocking drug. Br. J. Pharmac., 48, 340P. BROWN, H.C., CARRUTHERS, S.G., JOHNSTON, G.D., KELLY, J.G., McAINSH, J., McDEVITT, D.G. & SHANKS,
R.G. (1976). Clinical pharmacologic observations on atenolol a P-adrenoceptor blocker. Clin. Pharmac. Ther.
20,524-534.
CONWAY, F.J., FITZGERALD, J.D., McAINSH, J.,
ROWLANDS, D.J. & SIMPSON, W.T. (1976), Human pharmacokinetic and pharmacodynamic studies on atenolol (ICI 66082), a new cardioselective P-adrenoceptor blocking drug. Br. J. clin. Pharmac. 3, 267-272. GRAHAM, B.R., LITTLEJOHNS, D.W., PRICHARD, N.B.C., SCALES, B. & SOUTHORN, P. (1973). Preliminary obser-
vations on the human pharmacology of ICI 66082 in volunteers. Br. J. Pharmac., 49, 1 54P. HAINSWORTH, R., KARIM, F. & STOKER, J.B. (1974).
Blockade of peripheral vascular responses to isoprenaline by three ,6-adrenoceptor antagonists in the anesthetized dog. Br. J. Pharmac., 51, 161-168. HANSSON, L., ABERG, H., JAMESON, S., KARLBERG, B. & MALMERONA, R. (1973). Initial clinical experience with ICI 66082, a new P-adrenergic blocking agent, in hypertension. Acta Med. Scand., 194, 549-550. HARRY, J.D., KNAPP, M.F. & LINDEN, RJ. (1973). The action of ICI 66082 on the heart. Br. J. Pharmac., 48, 340P-341P.
HARRY, J.D., KNAPP, M.F. & LINDEN, RJ. (1974). The actions of a new ,8-adrenoceptor blocking drug, ICI 66082, on the rabbit papillary muscle and on the dog heart. Br. J. Pharmac., 51, 169-177. MALBICA, J.O., & MONSON, K.R. (1975). New and expedient determination of atenolol in biological samples. J. pharm. Sci., 64, 1992-1994. MATIN, S.B., WAN, S.H. & KARAM, J. (1974). Pharmacokinetics of tolbutamide in man: prediction by tolbutamide concentration in saliva. Clin. Pharmac. Ther., 16,1052-1058. McAINSH, J. (1977). Clinical pharmacokinetics of atenolol. Postgrad. med. J., 53, (Suppl. 3) 74-78. METZLER, C.M. (1969). NONLIN, a computer program for parameter estimation in nonlinear situations. Technical report 7292/69/7292/005. Kalamazoo, Michigan: The Upjohn Company. SASSARD, J., POZER, N., McAINSH, J., LEGHEARD, J. & ZECH, P. (1977). Pharmacokinetics of atenolol in
patients with renal impairment. Eur. J. clin. Pharmac., 12, 175-180. SHANKS, R.G., CARRUTHERS, S.G. KELLY, J.G. & McDEVITT, D.G. (1977). Correlation of reduction of exercise heart rate with blood levels of atenolol after oral
and intravenous administration. Postgrad. med. J., 53, (Suppl. 3) 70-73. WAN, S.H., MARONDE, R.F. & MATIN, S.B. (1978). GLC determination of atenolol and some fl-blocking agents from biological fluids. J. pharm. Sci., 67, 1340-1342. WAN, S.H., MATIN, S.B. & AZARNOFF, D.L. (1978). Pharmacokinetics, salivary excretion of amphetamine isomers, and effect of urine pH. Clin. Pharmac. Ther., 23, 585-590.
(Received July 13, 1978)
PHARMACOKINETICS, PHARMACOLOGY OF ATENOLOL AND EFFECT OF RENAL DISEASE S.H. WAN, R.T. KODA & R.F. MARONDE The Schools of Pharmacy and Medicine, Section of Clinical Pharmacology, University of Southern California and the Los Angeles County/USC Medical Center, Los Angeles, California
I The pharmacokinetics of intravenous and oral atenolol (50 mg) in six healthy volunteers was studied. Plasma, saliva and urine were collected up to 24 h after each dose. 2 There was no significant difference in atenolol half-life when administered by the two routes. Bioavailability of the orally administered atenolol was 50%. 3 Atenolol levels in saliva required about 2 h to reach equilibrium with plasma drug levels. 4 A comparison between the pharmacokinetics and pharmacology of atenolol was made in twelve healthy subjects. 5 Dose-independent pharmacokinetics were observed. Reductions in resting heart rate and arterial blood pressure were proportional to either the logarithm of dose or area under the plasma concentration time curve or cumulative urinary atenolol excretion. 6 Plasma elimination half-life in five subjects with renal failure was prolonged.
Introduction Atenolol [4-(2'-hydroxy-3'-isopropylaminopropoxy) phenyl acetamide] is a P-adrenoceptor blocking agent with antihypertensive properties (Amery, Billiet, Joossens, Meekers, Reybrouk & Van Mieghem, 1973; Graham, Littlejohns, Prichard, Scales & Southorn, 1973; Hansson, Aberg, Jameson, Karlberg & Malmerona, 1973). Its pharmacological properties have been compared in animals with those of propranolol and practolol ( Barrett, Carter, Fitzgerald, Hill & Le Count, 1973; Hainsworth, Karim & Stoker, 1974; Harry, Knapp & Linden, 1973). The fiadrenoceptor blocking effects of orally administered atenolol have been compared with the effects of similar doses of propranolol in human volunteers (Harry, Knapp & Lindin, 1974). The effects of atenolol indicated a preferential blockade of cardiac fiadrenoceptors with potency similar to propranolol. It does not possess membrane stabilizing properties and intrinsic sympathomimetic activity. The limited pharmacokinetic studies that have been performed in man indicate a half-life of about 6 h following a 100 mg oral dose with 45% of the oral dose excreted in urine by 48 h (Brown, Carruthers, Johnston, Kelly McAinsh, McDevitt & Shanks, 1976; Conway, Fitzgerald, McAinsh, Rowlands & Simpson, 1976; McAinsh, 1977). The present study was performed to further elucidate the pharmacokinetic behavior of atenolol in healthy subjects and in subjects with renal disease; and to assess any effects that single oral doses of 0306-5251/060569-06 $01.00
atenolol might have on resting heart rate and blood pressure of healthy volunteers.
Methods
Study 1: Comparison of intravenous and oral administration Six healthy male volunteers, ages 22-27 years, weighing between 64.5 to 79.9 kg (mean weight 72.9 kg) participated in this study. Each subject underwent a complete examination including a screening history, physical examination, 12 lead electrocardiogram and laboratory tests on blood and urine. Subjects were excluded if there was a history or evidence of diabetes or asthma, haematological, cardiovascular, gastrointestinal, hepatic or renal disease. Subjects with significant physical or laboratory abnormality and recent medication were also excluded. Qualified subjects were then hospitalized for the duration of the study. Following an overnight fast, and approximately 45 min before drug administration, subjects drank 500 ml water to ensure adequate urine output. Each subject received, on two separate occasions at least 72 h apart, 50mg atenolol as a rapid intravenous injection and orally as a 50 mg tablet (supplied by ICI, USA) with 120 ml water. A standard house diet was served 2-3 h after dosing. Blood, mixed saliva and all c Macmillan Joumals Ltd
1979
570
S.H. WAN, R.T. KODA & R.F. MARONDE
urine was collected at specified intervals up to 24 h. To avoid repeated venipuncture, blood was withdrawn from an indwelling catheter, inserted into a superficial vein in the forearm, into heparinized tubes.
Study 2: Comparison of 25, 50 and 100 mg oral doses Twelve healthy male volunteers, ages 21 to 36 years and weighing between 64.5 to 87.6 kg (mean weight 68.6 kg) participated in this study. The screening procedure for subject selection was similar to that described in Study 1. Each subject received on three separate occasions, tablets containing 25, 50 or 100 mg atenolol together with 100 ml water following an overnight fast. The 25 mg dose was given in the first dosing period followed by 50mg in the second dosing period and 100 mg in the third dosing period. The interval between each dose was a miniimum of 72 h. Subjects were allowed moderate activity except during blood pressure measurements and when blood samples were withdrawn. At specified intervals, resting heart rate and supine blood pressure were measured after 10 min rest in the recumbent position. Standing blood pressure was recorded immediately after assuming the standing position. Blood was obtained pre-drug and at specified times after drug administration up to 24 h. All urine was collected at 24 h intervals for a period of 72 h. Plasma and urine was frozen until analysis.
Study 3: Effect of renal disease Six hypertensive subjects, four males and two females with impaired renal function participated in this study. Subjects were between 35 and 64 years of age and
Table 1
weighed between 69.9 and 99.9 kg (mean weight 76.5 kg). Creatinine clearance was between 15 and 42 ml/min. The protocol for drug administration was similar to that described in Study 1. A single 50 mg oral dose was administered to the patient in addition to other medication listed in Table 1. Blood was obtained at appropriate intervals up to 48 h and all urine was collected at 12 and 24 h postdrug for determination of atenolol concentration. Subjects in all three studies were informed of the nature of the study, the duration and type of hazards to be expected and written consent obtained. Atenolol concentration in saliva, plasma and urine was measured by a gas chromatographic technique (Malbica & Monson, 1975; Wan, Maronde & Matin, 1978).
Results
Comparison ofintravenous and oral administration Mean (s.e. mean) plasma and saliva atenolol concentration following intravenous and oral administration is shown in Figures 1 and 2. The plasma concentration data following intravenous administration reflected a three compartment open model of the following form: C(t) = Pe"t + Aeat + Be-t
Where C(t) is plasma atenolol concentration at time t; P, A, B are coefficients and ,r, a, ,B are hybrid rate constants. Mean plasma atenolol concentrations were fitted to the above model using a least squares iterative method (14) with a weighting factor of 1/(concentra-
Clinical and pharmacokinetic data for subjects with renal failure
% of dose
Subject
Sex
1
M
2
F
3 4 5 6
F M M M
Medication
a-methyidopa, flurazepam, prochlorperazine, acetaminophen, aluminium hydroxide gel, frusemide, clonidine guanethidine, clonidine, hydralazine, frusemide, digoxin guanethidine, hydrochlorothiazide, allopurinol a-methyidopa, hydrochlorothiazide, insulin a-methyidopa, frusemide clonidine, hydrochlorothiazide, hydralazine, insulin
*
Not available
Haff-life (h) NA
28.0 21.4 13.72 10.98 14.03
excreted in 24 h 7.72 33.7
28.4
29.1 35.1 39.5
Creatinine clearance
(ml/min) 2.06 19.80
13.25 45.65 18.17 19.25
EFFECT OF RENAL DISEASE ON ATENOLOL PHARMACOKINETICS
571
5
E 0,
1
C
0
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0
c
-5 0 c
0
:
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0.05F I
I.
I
0
4
8
12
16
20
24
Time (h) 0.01
i
L L-
I
0
4
8
12
16
I
20
I
24
Figure 2 Mean (s.e. mean) plasma (-) and saliva (0) concentration of atenolol following oral administration of 50 mg atenolol in healthy volunteers, (n=6).
Time (h)
Figure 1 Mean (s.e. mean) plasma (S) and saliva (0) concentration of atenolol following intravenous administration of 50 mg atenolol in healthy volunteers, (n = 6).
tion)2 and the continuous line in Figure 1 represents the computer drawn curve which is given by: C (ng/ml) = 1615e-5.10 h-'t +
150oe-0881 h-'t
+
8OOe0- 130 h-'t
The close proximity of the observed data to the fitted curve indicates a good fit for the proposed model and the mean terminal half-life of 5.33 h is in reasonable agreement with the mean half-life of 6.06 h reported in previous studies (Brown et al., 1976). Peak plasma atenolol levels were reached at about 3 h following oral administration of drug. The expected triphasic decline was masked by the absorption phase and only a biphasic drug concentration decline was observed. The mean terminal half-life of 4.88 h after oral administration was not significantly different from the half-life of 5.33 h after intravenous dosing (P> 0.05). Both urinary excretion data and area under the plasma concentration-time curves (AUC) indicate a bioavailability of about 50% for the oral dose. At 24 h
the percent of the dose excreted in urine was 102.0 (s.d. 17.1) and 50.2 (s.d. 16.3) for the intravenously and orally administered drug respectively, while the AUC was 7888 (s.d. 1976) and 4113 (s.d. 1563) ng h ml-'. AUC was calculated by the trapezoidal method. Saliva atenolol concentration required about 2 h to reach equilibrium with plasma drug levels and an equilibrium saliva/plasma concentration ratio of 0.47 (s.d. 0.23) and 0.41 (s.d. 0.29) were reached during the intravenous and oral studies. Once equilibrated, saliva concentration decline paralleled that of plasma and half-lives determined from saliva atenolol concentrations were 5.25 h and 3.60 h for the intravenous and oral studies respectively. The latter value is subject to considerable error since the estimate was based on only two data points. Because salivary drug levels are much lower than plasma levels and do not reflect the latter during the lengthy equilibration phase, salivary drug measurements are probably not useful for pharmacokinetic studies of this drug, but may still be useful for monitoring steady-state drug levels during chronic dosing and for assessing patient compliance. According to previous studies (Matin, Wan & Karam, 1974; Wan, Matin & Azarnoff, 1978) the equilibrium saliva/plasma drug concentration ratio is a function of drug protein binding in saliva and plasma, pKa of drug and pH difference between saliva and plasma if passive diffusion is the primary mechanism of transfer of drug between plasma and saliva. Atenolol is a
S.H. WAN, R.T. KODA & R.F. MARONDE
572
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12
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20
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Figure 3 Mean (s.e. mean) plasma concentration of atenolol following oral administration of 25 (0), 50 (A) and 100 (U) mg atenolol in healthy volunteers, (n= 12).
relatively hydrophilic compound. The low
saliva/plasma ratio for atenolol observed in the present study suggests that partition coefficient could also be a factor in determining this ratio. Table 2
Comparison of25, 50 and 100 mg oral doses Mean (s.e. mean) plasma concentration of atenolol at doses of 25, 50 and 100 mg is presented in Figure 3. Data for the 100 mg dose represents only eleven subjects since one individual who had exhibited bradycardia at the 50 mg pre-dose period and during the 25 and 50 mg dose periods was not administered the 100 mg dose. Estimates of the pharmacokinetic parameters for this study are presented in Table 2. Good estimates of the various pharmacokinetic parameters at the 50 and 100 mg dose were obtained. In the case of the 25 mg dose, measurable atenolol levels were not present for many subjects at 0.5 h and beyond 8 h and the data for this study were not subjected to non-linear regression analysis. Peak plasma concentrations were proportional to dose at the 25 and 50 mg dose level but were low for the 100 mg dose indicating smaller percentage absorption with the latter dose which is confirmed by cumulative excretion in urine of 36.6% versus 48.0% and 40.7% for the 25 and 50 mg doses. Renal clearance was obtained by dividing the total amount of drug excreted in urine by AUC. Both the AUC and renal clearance do not indicate any trend related to dose. Formulation differences between the 25, 50 and 100 mg doses are a possible explanation for the lower absorption with the 100 mg dose. In Table 3, a comparison between doses is made for relative reductions in mean resting heart rate and arterial blood pressures at the time of peak plasma concentration. In designing the study protocol, resting heart rate measurements were primarily intended as a monitor of drug safety and possible cardiotoxicity rather than degree of fi-adrenoceptor blockade which is better assessed by maxiimum exercise tachycardia (Amery, DePlaen, Lijnen, McAinsh & Reybrouk, 1977; Matin et al., 1974; Shanks, Carruthers, Kelly & McDevitt, 1977). At the time of peak plasma levels, both the resting heart rate and blood pressure were decreased. The percent reductions were essentially
Mean pharmacokinetic parameters of subjects administered 25, 50 and 100 mg atenolol
Dose (mg) Parameter
Elimination T, (h) AUC*(tg h ml-') 0-24 h 0-co h Renal clearance (I/h) 0-24 h 0-co h Percent of dose excreted in urine 0-24 h 0-72 h I
Area under plasma concentration time curve
25
50
100
0.840 0.856
7.23 2.41 2.64
6.12 3.95 4.23 8.50 8.64
12.7 14.0 42.7 48.0
7.58 7.70 36.5 40.7
33.6 36.6
EFFECT OF RENAL DISEASE ON ATENOLOL PHARMACOKINETICS
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20.4 36.6
5.5
Amount excreted (mg)
Figure 4 Relationship between percent reductions in heart rate (A), supine arterial pressure (0), standing arterial pressure (0) and the logarithm of dose, AUC and cumulative drug excretion, (n= 12).
Pharmacokinetics in renal disease 1.0
Mean (s.e. mean) plasma atenolol concentrations for subjects with moderate to severe renal failure are given in Figure 5 and some pertinent clinical and pharmacokinetic data are presented in Table 1. Figure 5 represents data from only five subjects since subject 1 subsequently underwent dialysis and the data for this subject are not included. As expected, since renal excretion is the major route of elimination, a marked prolongation in terminal half-life was observed in this group of patients, with a half-life range of 10.13-28.0 h which is in accord with previously published observations (Sassard, Pozer, McAinsh, Legheard & Zech, 1977). At the same time 24 h urinary excretion of atenolol dropped to a mean of 28.9 (s.d. 4.56) percent of the dose.
0.5
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Figure 5 Mean (s.e. mean) plasma atenolol centration in subjects with renal failure, (n = 5).
con-
proportional to the logarithm of dose (Figure 4). A linear relationship was also obtained between the relative reduction of heart rate and blood pressure and the logarithm of AUC and cumulative excretion of drug in urine. In this case it is probably more accurate to use AUC and cumulative drug excretion since the extent of absorption appears to be dose related. AUC and cumulative drug excretion reflect the amount of drug absorbed whereas dose does not.
Table 3 Percent reductions in mean heart rate and blood pressure 2 h after the oral administration of 25, 50 and 100 mg of atenolol
Atenolol (mg) 100 50 % reduction % reduction % reduction 25
Heart rate 4.6 (beats/min) Supine blood pressure 2.8 Systolic 0.0 Diastolic 0.9 Arterial Standing blood pressure 8.4 Systolic 0.9 Diastolic 3.3 Arterial
7.2
10.9
8.0 4.9 6.0
10.4 6.9 8.0
9.3 5.0 6.4
11.7 6.1 8.0
574
S.H. WAN, R.T. KODA & R.F. MARONDE
References AMERY, A., DePLAEN, J., LIJNEN, P., McAINSH, J. &
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CONWAY, F.J., FITZGERALD, J.D., McAINSH, J.,
ROWLANDS, D.J. & SIMPSON, W.T. (1976), Human pharmacokinetic and pharmacodynamic studies on atenolol (ICI 66082), a new cardioselective P-adrenoceptor blocking drug. Br. J. clin. Pharmac. 3, 267-272. GRAHAM, B.R., LITTLEJOHNS, D.W., PRICHARD, N.B.C., SCALES, B. & SOUTHORN, P. (1973). Preliminary obser-
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Blockade of peripheral vascular responses to isoprenaline by three ,6-adrenoceptor antagonists in the anesthetized dog. Br. J. Pharmac., 51, 161-168. HANSSON, L., ABERG, H., JAMESON, S., KARLBERG, B. & MALMERONA, R. (1973). Initial clinical experience with ICI 66082, a new P-adrenergic blocking agent, in hypertension. Acta Med. Scand., 194, 549-550. HARRY, J.D., KNAPP, M.F. & LINDEN, RJ. (1973). The action of ICI 66082 on the heart. Br. J. Pharmac., 48, 340P-341P.
HARRY, J.D., KNAPP, M.F. & LINDEN, RJ. (1974). The actions of a new ,8-adrenoceptor blocking drug, ICI 66082, on the rabbit papillary muscle and on the dog heart. Br. J. Pharmac., 51, 169-177. MALBICA, J.O., & MONSON, K.R. (1975). New and expedient determination of atenolol in biological samples. J. pharm. Sci., 64, 1992-1994. MATIN, S.B., WAN, S.H. & KARAM, J. (1974). Pharmacokinetics of tolbutamide in man: prediction by tolbutamide concentration in saliva. Clin. Pharmac. Ther., 16,1052-1058. McAINSH, J. (1977). Clinical pharmacokinetics of atenolol. Postgrad. med. J., 53, (Suppl. 3) 74-78. METZLER, C.M. (1969). NONLIN, a computer program for parameter estimation in nonlinear situations. Technical report 7292/69/7292/005. Kalamazoo, Michigan: The Upjohn Company. SASSARD, J., POZER, N., McAINSH, J., LEGHEARD, J. & ZECH, P. (1977). Pharmacokinetics of atenolol in
patients with renal impairment. Eur. J. clin. Pharmac., 12, 175-180. SHANKS, R.G., CARRUTHERS, S.G. KELLY, J.G. & McDEVITT, D.G. (1977). Correlation of reduction of exercise heart rate with blood levels of atenolol after oral
and intravenous administration. Postgrad. med. J., 53, (Suppl. 3) 70-73. WAN, S.H., MARONDE, R.F. & MATIN, S.B. (1978). GLC determination of atenolol and some fl-blocking agents from biological fluids. J. pharm. Sci., 67, 1340-1342. WAN, S.H., MATIN, S.B. & AZARNOFF, D.L. (1978). Pharmacokinetics, salivary excretion of amphetamine isomers, and effect of urine pH. Clin. Pharmac. Ther., 23, 585-590.
(Received July 13, 1978)
