Journdl o f Pharmacokinetics and Biopharmaceutics, Vol. 4, No. 3, 1976
Pharmacokinetics of the Antiarrhythmic Disopyramide in Healthy Humans Peter H. Hinderling 1 and Edward R. Garrett 1'2 Received Sept. 19, 1975--Final Dec. 30, 1975 The pharmacokinetics of the antiarrhythmic disopyramide, 4-diisopropylamino-2-phenyl-2-(2pyridyl)butyramide phosphate, and its monodealkylated metabolite were investigated in seven volunteers after intravenous (1 and 2 mg/kg) and oral (3 and 6 mg/kg) administration. Unchanged drug (52%) and the monodealkylated metabolite (25%) were renally excreted on intravenous administration. The pharmacokinetics of disopyramide were first order and dose independent only when referenced to the drug not bound to plasma proteins since this binding was dose dependent. The apparent half-lives of the ct and fl phases on intravenous administration were 2 rain and 4.5 hr, respectively. The apparent volumes of distribution of the central and peripheral compartments, referenced to unbound disopyramide in the plasma, were 9 and 80 liters, respectively. The.half-life of absorption of oral aqueous disopyramide phosphate was 30 rain with a lag time of 16 min and an apparent first-pass metabolism of 16 % of the absorbed dose, consistent with the hepatic efficiency of 14 %. The renal and metabolic clearances were 125 and 111 ml/min, respectively. Graphical and computer analysis of the plasma and urine data showed dose-independent first-order pharmacokinetics of plasma unbound drug in a two-compartment-body model to give two metabolites and a first-pass transformation of a fraction of the oral dose. The absorption efficiency of unchanged drug was 83 %.
KEY WORDS: disopyramide; antiarrhythmic; pharmacokinetics. INTRODUCTION Disopyramide, 4-diisopr0pylamino-2-phenyl-2-(2-pyridyl)butyramide, is m a r k e t e d in E u r o p e as t h e b a s e ( R h y t h m o d a n ) . H~C\ /
~O[ CH
\
H3C
N--CH2--CH2--C--C--NH 2 R/
@N
DP: R = (CH3)2--CH
MI:R=H Supported in part by Grant No. NIH-RR-82 from the National Institutes of Health, Bethesda, Maryland, and by an unrestricted grant from Searle Laboratories, Skokie, Illinois. 1The Beehive, College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610. 2Address reprint requests to Edward R. Garrett, College of Pharmacy, Box 779, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610. 9 1976Plenum PublishingCorporation, 227 West 17th Street. New York, N.Y. 10011. No part of this publication may be reproduced, stored in a retrievalsystem,or transmitted, in any formor by any means,electronic,mechanical, photocopying, microfilming,recording, or otherwise,withoutwritten permissionof the publisher.
200
Hinderling and Garrett
It has been shown to be an effective quinidine-like (1--4) antiarrhythmic agent in experimentally induced arrhythmias in animals and in disorders of the impulse generation in man (5-11). The purpose of this study was to determine the pharmacokinetics of disopyramide administered as the phosphate salt and its major metabolite M 1, 4-isopropylamino-2-phenyl-2-(2-pyridyl)butyramide (12), in healthy humans after intravenous and oral administration of the parent drug at various dosage levels. Pharmacokinetic data for disopyramide in the rat, dog, and man were reported by Ranney et al. (13), but the employed fluorometric assay did not differentiate between the parent drug and occurring metabolite(s). The recent availability of a specific gas chromatographic assay for disopyramide and its major metabolite (14) has made this present study possible. MATERIALS AND M E T H O D S Materials
The following were used: Disopyramide phosphate in sterile aqueous soltition was supplied by the manufacturer (Searle Laboratories, Skokie, Ill.). Heparin (Sodium Heparin Injection USP, Upjohn Co., Kalamazoo, Mich.) was used to prevent coagulation Criteria for Volunteer Selection
Seven healthy male Caucasian volunteers between 21 and 25 years of age were selected. An individual was considered healthy when there were no history of disease of the cardiovascular system, kidney, liver, blood, gastrointestinal tract, or endocrine organs, no prostatic hypertrophy, no drug addiction, and no alcoholism. The volunteers had a normal status, EKG, blood pressure, and x-ray (chest). The following initial laboratory checkup was performed in each of the volunteers: complete blood count (hematocrit included), sedimentation rate, serum electrophoresis, creatinine clearance, urinalysis, bilirubin, SGOT, SGPT, alkaline phosphatase, and serum electrolytes: Na, K, Ca, inorganic PO 4. The following tests were repeated prior to the second, third, and fourth study on each individual to determine adverse drug effects or clinical changes due to the experimental procedures: complete blood count (hematocrit included), sedimentation rate, serum electrophoresis, serum creatinine, serum electrolytes. Pharmacokinetic Procedures
Four different studies were performed in each of the seven volunteers which included intravenous administration of 1 and 2 mg/kg ofdisopyramide
Pharmacokinetics of the Antiarrhythmic Disopyramide in Healthy Humans
201
phosphate in solution and oral administration of 3 and 6 mg/kg of drug in solution. A total of 28 studies were conducted with an incomplete latin square design. Intervals of 3 weeks were maintained between studies in a subject to exclude any possible enzyme induction due to the repeated administration of the drug. The volunteers were supine during the first 24 hr after the administration of the drug. Later they were ambulatory, although no exercise was allowed. The individuals were fasted 12 hr before drug administration in both the i.v. and p.o. experiments. After the administration of the drug, the volunteers fasted 8 hr in the oral and 4 hr in the intravenous experiments. Within the first 24 hr after drug administration, the food intake was restricted to fluids, e.g., soups, milkshakes, and other beverages. The calorie intake was balanced in all studies to maintain constant weight. The daily intake was fixed at 2500 ml/24 hr. No beverage or food containing caffeine or other diuretically effective substances was allowed. Three hours prior to administration of the drug, the volunteers received a peroral water loading (10 ml/kg). One hour before the drug was given, a butterfly needle (Abbott Laboratories, North Chicago, Ill.) was placed in a cubital vein. A constant drip of 0.45~o sodium chloride solution (Baxter Laboratories, Division of Travenol Laboratories, Inc., Morton Grove, Ill.) to keep the vein open and to abet a minimum urine flow, 1.7 ml/min in the oral experiments and 1.5 ml/min in the i.v. experiments, was started immediately through the butterfly needle. In the i.v. experiments, a catheter (Intracath, Deseret Pharmaceutical Co., Sandy, Utah) was placed in the cubital vein of the other side and a constant drip of 0.9 ~ sodium chloride solution (2.0 ml/min) was started immediately through the catheter. Both infusion solutions contained heparin 1000 IU/1000 mt, in order to prevent coagulation. Both the butterfly needle and the catheter were removed 11 hr after the administration of the drug. Later blood samples were taken by venipuncture. The freshly prepared drug solutions in 0.9 ~ sodium chloride solution were assayed. They were intravenously administered at a constant rate for 1 min through the catheter, which was immediately flushed with 20 ml 0.9 ~o sodium chloride solution, which time was considered as time zero. They were administered orally by a syringe followed by immediate swallowing to avoid sublinguai or buccal absorption. A 40-ml water rinse was swallowed immediately. Blood (10ml) was taken through the butterfly needle with syringes using a three-way stopcock (Tomac, American Hospital Supply, Evanston, Ill.) within 10 sec at 0, 1.5, 2, 2.5, 3, 5, 7, 10, 12, 15, 30, 45, 60, and 90 min and at 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 24, and 36 hr after i.v. administration of the drug and at 0, 2.5, 5, 10, 15, 30, 45, 60, 75, and 90min and at 2, 2.5, 3, 4, 5, 8, 10, 12, 24, and 36 hr after oral administration. An initial 2 ml of blood
202
Hinderling and Garrett
was discarded. The samples were immediately transferred to glass tubes (Vacutainer, Becton-Dickinson, Rutherford, N.J.) containing ethylenediaminetetraacetate to prevent coagulation. After centrifugation at 1500 rpm for 20 min within 1 hr after sampling, the plasma was transferred to storage tubes and deep frozen until assayed. In both the i.v. and oral experiments, total volumes of urine were obtained for the following collection periods: - 3 - 0 , 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-18, 18-24, 24-48, and 48-72 hr after drug administration. The pH was monitored and aliquots were transferred to storage containers and deep frozen until assayed.
Analytical Procedures The gas chromatographic assay for the drug and its major monodealkylated metabolite included use of a flame ionization detector (14). The lower levels of sensitivity were 0.085 #g/ml and 0.065 #g/ml for the parent drug and 0.17 #g/ml and 0.125 #g/ml for the metabolite in plasma and urine, respectively. Mean and standard deviation of repetitively determined known serum concentrations of disopyramide of 1.18 and 0.3 #g/ml were, respectively, 1.14 _+ 0.11 #g/ml (n = 42) and 0.29 __+0.03 #g/ml (n = 44). In urine spiked with disopyramide to give concentrations of 7.50 and 1.50 /~g/ml, the respective values of the mean and standard deviation were 7.51 + 0.46 #g/ml (n = 26)and 1.42 _+ 0.19 #g/ml (n = 26). Plasma assays were conducted for disopyramide in only three of the volunteers at all doses i.v. and p.o., although urine assays were conducted for all studies in all volunteers. The monodealkylated metabolite was monitored in all urines but only in the plasma of these three subjects receiving the higher oral dose. RESULTS The plus and minus values for mean values given hereafter in the text refer to the standard error a/w/n of such means, where ~ is the standard deviation given in the tables and n is the number of values considered.
Plasma Pharmacokinetics of Disopyramide After Intravenous Administration The binding of disopyramide to human plasma protein is saturable and the fraction bound varies from 0.05 to 0.65 with decreasing drug concentration (15). A high concentration of the monodealkylated metabolite decreased the binding of the parent drug and vice versa. However, the concentrations of the monodealkylated metabolite found in these acute studies were sufficiently low so as not to affect the disopyramide protein binding
Pharmacokinetics of the Antiarrhythmic Disopyramide in Healthy Humans
203
significantly. In order to avoid the nonlinear pharmacokinetics of disopyramide which would result if the total plasma concentrations of drug, [Ap], were to be considered (16), the pharmacokinetic evaluations were based on the concentrations of unbound disopyramide in the plasma, [A~] = f,[Ap], where the fraction unbound,f,, was known (15) for a particular total plasma concentration. In a previous publication on disopyramide plasma levels (13), they were described in terms of total plasma concentration. The concentrations of unbound disopyramide in plasma were fitted against time by the method of residuals (17a) (Fig. 1) [A~] = Ae-~'t + Be -st
(1)
The evaluated parameters for the various studies are given in Table I.
0
fi -I
E ~-
A'*
'r
E
" '~
--------
I
a
0
0 ~
0 "-------- 0
4"5
6'0
90
I
O
w
I*---(3[
.(3 E
g o
Ill
O
I t I
0.
I,
15
B ~a~.o o ~ \
3'0
120
Minutes
Oo
o 0
"
O
0.t
m
12
18
Hours
Fig. 1. Semilogarithmic plot of unbound disopyramide plasma concentrations following intravenous administration of 2 mg/kg disopyramide phosphate to subject B. The antilogarithmic values of the terminal linear slope fl were subtracted from the initial data points and these feathered data points were fitted to a straight line of slope ~. [A~]0 is the sum of the intercepts (A + B) of the extrapolated lines with slopes c~ and fl, respectively. The inset is for an expanded time scale. Key: O, original data; T, feathered values.
-
(UM,)~]/O
(Cl~,)tot,e ml/min, i.v. : graphical (analog) 1 0 3 k r j sec- 1, i.v. lOaknr, g sec-1, i.v. 103knv,h sec- 1, i.v. 103knu, ~ sec- ~, i.v. 10~kaM,j sec-1, i.v. lOakaM2J sec-1, i.v. Va!~,~liters, i.v. Vr~,k liters, i.v. (CI~),,,,' ml/min, i.v. (Cl~)m,t," ml/min, i.v. (CI~),,~," ml/min, i.v. (p.o.) Absorption lag timefl min, p.o. 103k6x.B,p see- 1, p.o. 10aka~.Bfl sec-~, p.o. lOSkoi,M~fl sec- l, p.o.
= IOZ(M2)~/D ;a i.v. (p.o.)
(Ups)|
291 (246) 0.83 (0.65) 6.35 (4.47) 0.33 (0.22) 0.26 (0.18) 0.12 (0.09) 0.14 (0.10) 71 (81) 63 (71) 161 (137) 130 (109) 166(135) 18 (10) 0.43 (0.21) 0.13 0.03
23.9 (20.5)
27.7 19.7 (46.1) 0.23 0.18 (0.26) 0.18 (0.14) 10.8 8.7 (8.2) 1.20 1.08 (1.31) 8.3 (10.3) 55.2 (43.8) 20.9 (35.7)
a,~ hr- 1, i.v. : graphical Computer: analog (digital) fl,~ hr- 1, i.v., plasma : graphical Computer: analog (digital) fl,a h r - l , urine; i.v. (p.o.): graphical A,~ % of dose/liter, i.v. : graphical Computer: analog (digital) Bfl % of dose/liter, i.v. : graphical Computer: analog (digital) V~,b liters, i.v, : graphical (analog) I02(UDe)~/D; c i.v. (p.o.) I 0 2 ( U u , ) j D ;c i.v. (p.o.)
102[D -
49.3 (157.5)
233 (235) 0.76 (0.68) 6.58 (5.77) 0.27 (0.26) 0.18 (0.15) 0.13 (0.11) 0.05 (0.05) 84 (91) 75 (81) 142 (148) 91 (88) 160(107) 15 (10) 0.55 (0.32) 0.19 0.04
10.2 (23.7)
27.7 24.6 (26.5) 0.16 0.15 (0.17) 0.14 (0.15) 10.5 9.5 (8.2) 1.00 0.99 (1.02) 8.7 (9.5) 60.8 (41.9) 29.0 (34.4)
235 (198) 0.82 (0.60) 8.58 (5.22) 0.28 (0.20) 0.27 (0.18) 0.14 (0.10) 0.13 (0.09) 84 (83) 76 (75) 119 (105) 115 (93) 111(152) 9 (8) 0.26 (0.17) 0.16 0.03
22.4 (31.6)
35.6 22.2 (31.7) 0.16 0.14 (0.17) 0.14 (0.15) 12.8 10.6 (12.8) 1.09 1.07 (1.13) 7.2 (8.6) 50.9 (36.2) 26.7 (32.2)
51.6 (157.1)
1.72
239 (231) 0.87 (0.61) 7.61 (5.13) 0.19 (0.21) 0.20 (0.21) 0.12 (0.13) 0.08 (0.08) 86 (87) 76 (78) 114 (116) 124 (115) 135(179) 9 (0) 0.41 (0.32) 0.22 0.07
19.9 (27.6)
27.7 22.0 (28.6) 0.16 0.15 (0.20) 0.15 (0.16) 8.8 9.8 (9.0) 0.95 1.02 (1.09) 10.2 (9.2) 48.0 (37.4) 32.1 (34.8)
92.3 (302.3)
B (64.1, 16.7)
234 (186) 0.45 (0.56) 6.39 (4.28) 0.27 (0.17) 0.25 (0.15) 0.11 (0.06) 0.14 (0.09) 116 (83) 108 (73) 121 (99) 112 (87) 87(85) 27 (27) 0.11 (0.14) 0.16 0.01
27.2 (26.2)
24.9 18.5 (23.4) 0.12 0.13 (0.13) 0.12 (0.1 I) 12.0 9.4 (10.1) 1.08 1.08 (1.18) 7.6 (9.5) 51.9 (48.4) 20.9 (25.4)
66.7 (191.7)
237 (211) 0.82 (0.68) 6.57 (5.47) 0.18 (0.16) 0.21 (0.18) 0.08 (0.07) 0.15 (0.11) 91 (95) 80 (85) 110 (101) 87 (99) 93(73) 15 (8) 0.15 (0.07) 0.10 0.01
32.7 (19.7)
27.7 23.2 (13.6) 0.15 0.13 (0.13) 0.12 (0.10) 9.0 8.6 (3.6) 0.99 0.95 (0.91) 10.1 (10.5) 46.4 (51.0) 20.9 (29.3)
125.7 (354.6)
2.04
C (79.7, 187)
Parameters for Disopyramide Pharmacokinetics
95.5 (298.0)
1.77
Surface area, m 2 :
D, dose, mg: i.v. (p.o.):
A (65.3, 173)
I.
Subject (kg, era):
Table
245 + 23 (218 _+ 23) 0.76 + 0.16(0.63 +- 0.05) 7.00 + 0.91 (5.06 +- 0.58) 0.25 + 0.06 (0.20 +- 0.04) 0.23 + 0.04(0.18 +- 0.02) 0.12 _+ 0.02 (0.09 +- 0.03) 0.12 + 0.04 (0.09 • 0.02) 89 +- 15 (87 + 5) 80_+ 15(77 + 5 ) 129 + 20(118 +_ 20) 111 + 18(99_+ 11) 125 ,+ 34(122 + 41) 1 6 + 7 ( 1 1 +_9) 0.32 +_ 0.18 (0.21 + 0.10) 0.16 +- 0.04 0.03 + 0.02
22.7 + 7.6 (24.9 + 4.5)
28.6 +_ 3.6 21.7 +- 2.3 0.16 + 0.04 0.15 + 0.02 0.14 +_ 0.02(0.14 + 0.02) 10.7 +- 1.6 9.4 _+ 0.7 1.05 _+ 0.09 1.03 + 0.05 8.7 + 1.3 (9.6 + 0.7) 52.2 +- 5.2 (43.1 +- 5.9) 25.1 + 4.9 (32.0 +- 4.0)
Average +- SD
el.
t~
B
D M2
unchanged and monodealkylated disopyramide, respectively. The parenthetical values are based on the kn~ values obtained by analog computer fitting. ~This overall steady-state volume of distribution was calculated from V~(ksr + krn)/krn since V~/V~ = krn/(ksr + krn), where the knr and kra values were obtained graphically. The parenthetical values are from analog computer obtained constants. The psendo-steady-state volumes of distribution calculated from (Clp)tot/fl averaged 80 +_ 4 and 95 _+ 12 for two different graphical estimates of(Cl~)to . and 89 _+ 6 for the analog computer obtained (Cl~)to~and were consistent with the steady-state volumes.
B
and they were calculated from kas~, = (UM,)~kB~/[D ~ (Un~)0o] and kn~ = = kau - kn~,, where (Una)~ and (U~,)~ are the total amounts of drug renally excreted as
M~ ~
,
Pharmacokinetics of the Antiarrhythmic Disopyramide in Healthy Humans Peter H. Hinderling 1 and Edward R. Garrett 1'2 Received Sept. 19, 1975--Final Dec. 30, 1975 The pharmacokinetics of the antiarrhythmic disopyramide, 4-diisopropylamino-2-phenyl-2-(2pyridyl)butyramide phosphate, and its monodealkylated metabolite were investigated in seven volunteers after intravenous (1 and 2 mg/kg) and oral (3 and 6 mg/kg) administration. Unchanged drug (52%) and the monodealkylated metabolite (25%) were renally excreted on intravenous administration. The pharmacokinetics of disopyramide were first order and dose independent only when referenced to the drug not bound to plasma proteins since this binding was dose dependent. The apparent half-lives of the ct and fl phases on intravenous administration were 2 rain and 4.5 hr, respectively. The apparent volumes of distribution of the central and peripheral compartments, referenced to unbound disopyramide in the plasma, were 9 and 80 liters, respectively. The.half-life of absorption of oral aqueous disopyramide phosphate was 30 rain with a lag time of 16 min and an apparent first-pass metabolism of 16 % of the absorbed dose, consistent with the hepatic efficiency of 14 %. The renal and metabolic clearances were 125 and 111 ml/min, respectively. Graphical and computer analysis of the plasma and urine data showed dose-independent first-order pharmacokinetics of plasma unbound drug in a two-compartment-body model to give two metabolites and a first-pass transformation of a fraction of the oral dose. The absorption efficiency of unchanged drug was 83 %.
KEY WORDS: disopyramide; antiarrhythmic; pharmacokinetics. INTRODUCTION Disopyramide, 4-diisopr0pylamino-2-phenyl-2-(2-pyridyl)butyramide, is m a r k e t e d in E u r o p e as t h e b a s e ( R h y t h m o d a n ) . H~C\ /
~O[ CH
\
H3C
N--CH2--CH2--C--C--NH 2 R/
@N
DP: R = (CH3)2--CH
MI:R=H Supported in part by Grant No. NIH-RR-82 from the National Institutes of Health, Bethesda, Maryland, and by an unrestricted grant from Searle Laboratories, Skokie, Illinois. 1The Beehive, College of Pharmacy, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610. 2Address reprint requests to Edward R. Garrett, College of Pharmacy, Box 779, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610. 9 1976Plenum PublishingCorporation, 227 West 17th Street. New York, N.Y. 10011. No part of this publication may be reproduced, stored in a retrievalsystem,or transmitted, in any formor by any means,electronic,mechanical, photocopying, microfilming,recording, or otherwise,withoutwritten permissionof the publisher.
200
Hinderling and Garrett
It has been shown to be an effective quinidine-like (1--4) antiarrhythmic agent in experimentally induced arrhythmias in animals and in disorders of the impulse generation in man (5-11). The purpose of this study was to determine the pharmacokinetics of disopyramide administered as the phosphate salt and its major metabolite M 1, 4-isopropylamino-2-phenyl-2-(2-pyridyl)butyramide (12), in healthy humans after intravenous and oral administration of the parent drug at various dosage levels. Pharmacokinetic data for disopyramide in the rat, dog, and man were reported by Ranney et al. (13), but the employed fluorometric assay did not differentiate between the parent drug and occurring metabolite(s). The recent availability of a specific gas chromatographic assay for disopyramide and its major metabolite (14) has made this present study possible. MATERIALS AND M E T H O D S Materials
The following were used: Disopyramide phosphate in sterile aqueous soltition was supplied by the manufacturer (Searle Laboratories, Skokie, Ill.). Heparin (Sodium Heparin Injection USP, Upjohn Co., Kalamazoo, Mich.) was used to prevent coagulation Criteria for Volunteer Selection
Seven healthy male Caucasian volunteers between 21 and 25 years of age were selected. An individual was considered healthy when there were no history of disease of the cardiovascular system, kidney, liver, blood, gastrointestinal tract, or endocrine organs, no prostatic hypertrophy, no drug addiction, and no alcoholism. The volunteers had a normal status, EKG, blood pressure, and x-ray (chest). The following initial laboratory checkup was performed in each of the volunteers: complete blood count (hematocrit included), sedimentation rate, serum electrophoresis, creatinine clearance, urinalysis, bilirubin, SGOT, SGPT, alkaline phosphatase, and serum electrolytes: Na, K, Ca, inorganic PO 4. The following tests were repeated prior to the second, third, and fourth study on each individual to determine adverse drug effects or clinical changes due to the experimental procedures: complete blood count (hematocrit included), sedimentation rate, serum electrophoresis, serum creatinine, serum electrolytes. Pharmacokinetic Procedures
Four different studies were performed in each of the seven volunteers which included intravenous administration of 1 and 2 mg/kg ofdisopyramide
Pharmacokinetics of the Antiarrhythmic Disopyramide in Healthy Humans
201
phosphate in solution and oral administration of 3 and 6 mg/kg of drug in solution. A total of 28 studies were conducted with an incomplete latin square design. Intervals of 3 weeks were maintained between studies in a subject to exclude any possible enzyme induction due to the repeated administration of the drug. The volunteers were supine during the first 24 hr after the administration of the drug. Later they were ambulatory, although no exercise was allowed. The individuals were fasted 12 hr before drug administration in both the i.v. and p.o. experiments. After the administration of the drug, the volunteers fasted 8 hr in the oral and 4 hr in the intravenous experiments. Within the first 24 hr after drug administration, the food intake was restricted to fluids, e.g., soups, milkshakes, and other beverages. The calorie intake was balanced in all studies to maintain constant weight. The daily intake was fixed at 2500 ml/24 hr. No beverage or food containing caffeine or other diuretically effective substances was allowed. Three hours prior to administration of the drug, the volunteers received a peroral water loading (10 ml/kg). One hour before the drug was given, a butterfly needle (Abbott Laboratories, North Chicago, Ill.) was placed in a cubital vein. A constant drip of 0.45~o sodium chloride solution (Baxter Laboratories, Division of Travenol Laboratories, Inc., Morton Grove, Ill.) to keep the vein open and to abet a minimum urine flow, 1.7 ml/min in the oral experiments and 1.5 ml/min in the i.v. experiments, was started immediately through the butterfly needle. In the i.v. experiments, a catheter (Intracath, Deseret Pharmaceutical Co., Sandy, Utah) was placed in the cubital vein of the other side and a constant drip of 0.9 ~ sodium chloride solution (2.0 ml/min) was started immediately through the catheter. Both infusion solutions contained heparin 1000 IU/1000 mt, in order to prevent coagulation. Both the butterfly needle and the catheter were removed 11 hr after the administration of the drug. Later blood samples were taken by venipuncture. The freshly prepared drug solutions in 0.9 ~ sodium chloride solution were assayed. They were intravenously administered at a constant rate for 1 min through the catheter, which was immediately flushed with 20 ml 0.9 ~o sodium chloride solution, which time was considered as time zero. They were administered orally by a syringe followed by immediate swallowing to avoid sublinguai or buccal absorption. A 40-ml water rinse was swallowed immediately. Blood (10ml) was taken through the butterfly needle with syringes using a three-way stopcock (Tomac, American Hospital Supply, Evanston, Ill.) within 10 sec at 0, 1.5, 2, 2.5, 3, 5, 7, 10, 12, 15, 30, 45, 60, and 90 min and at 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 24, and 36 hr after i.v. administration of the drug and at 0, 2.5, 5, 10, 15, 30, 45, 60, 75, and 90min and at 2, 2.5, 3, 4, 5, 8, 10, 12, 24, and 36 hr after oral administration. An initial 2 ml of blood
202
Hinderling and Garrett
was discarded. The samples were immediately transferred to glass tubes (Vacutainer, Becton-Dickinson, Rutherford, N.J.) containing ethylenediaminetetraacetate to prevent coagulation. After centrifugation at 1500 rpm for 20 min within 1 hr after sampling, the plasma was transferred to storage tubes and deep frozen until assayed. In both the i.v. and oral experiments, total volumes of urine were obtained for the following collection periods: - 3 - 0 , 0-2, 2-4, 4-6, 6-8, 8-10, 10-12, 12-18, 18-24, 24-48, and 48-72 hr after drug administration. The pH was monitored and aliquots were transferred to storage containers and deep frozen until assayed.
Analytical Procedures The gas chromatographic assay for the drug and its major monodealkylated metabolite included use of a flame ionization detector (14). The lower levels of sensitivity were 0.085 #g/ml and 0.065 #g/ml for the parent drug and 0.17 #g/ml and 0.125 #g/ml for the metabolite in plasma and urine, respectively. Mean and standard deviation of repetitively determined known serum concentrations of disopyramide of 1.18 and 0.3 #g/ml were, respectively, 1.14 _+ 0.11 #g/ml (n = 42) and 0.29 __+0.03 #g/ml (n = 44). In urine spiked with disopyramide to give concentrations of 7.50 and 1.50 /~g/ml, the respective values of the mean and standard deviation were 7.51 + 0.46 #g/ml (n = 26)and 1.42 _+ 0.19 #g/ml (n = 26). Plasma assays were conducted for disopyramide in only three of the volunteers at all doses i.v. and p.o., although urine assays were conducted for all studies in all volunteers. The monodealkylated metabolite was monitored in all urines but only in the plasma of these three subjects receiving the higher oral dose. RESULTS The plus and minus values for mean values given hereafter in the text refer to the standard error a/w/n of such means, where ~ is the standard deviation given in the tables and n is the number of values considered.
Plasma Pharmacokinetics of Disopyramide After Intravenous Administration The binding of disopyramide to human plasma protein is saturable and the fraction bound varies from 0.05 to 0.65 with decreasing drug concentration (15). A high concentration of the monodealkylated metabolite decreased the binding of the parent drug and vice versa. However, the concentrations of the monodealkylated metabolite found in these acute studies were sufficiently low so as not to affect the disopyramide protein binding
Pharmacokinetics of the Antiarrhythmic Disopyramide in Healthy Humans
203
significantly. In order to avoid the nonlinear pharmacokinetics of disopyramide which would result if the total plasma concentrations of drug, [Ap], were to be considered (16), the pharmacokinetic evaluations were based on the concentrations of unbound disopyramide in the plasma, [A~] = f,[Ap], where the fraction unbound,f,, was known (15) for a particular total plasma concentration. In a previous publication on disopyramide plasma levels (13), they were described in terms of total plasma concentration. The concentrations of unbound disopyramide in plasma were fitted against time by the method of residuals (17a) (Fig. 1) [A~] = Ae-~'t + Be -st
(1)
The evaluated parameters for the various studies are given in Table I.
0
fi -I
E ~-
A'*
'r
E
" '~
--------
I
a
0
0 ~
0 "-------- 0
4"5
6'0
90
I
O
w
I*---(3[
.(3 E
g o
Ill
O
I t I
0.
I,
15
B ~a~.o o ~ \
3'0
120
Minutes
Oo
o 0
"
O
0.t
m
12
18
Hours
Fig. 1. Semilogarithmic plot of unbound disopyramide plasma concentrations following intravenous administration of 2 mg/kg disopyramide phosphate to subject B. The antilogarithmic values of the terminal linear slope fl were subtracted from the initial data points and these feathered data points were fitted to a straight line of slope ~. [A~]0 is the sum of the intercepts (A + B) of the extrapolated lines with slopes c~ and fl, respectively. The inset is for an expanded time scale. Key: O, original data; T, feathered values.
-
(UM,)~]/O
(Cl~,)tot,e ml/min, i.v. : graphical (analog) 1 0 3 k r j sec- 1, i.v. lOaknr, g sec-1, i.v. 103knv,h sec- 1, i.v. 103knu, ~ sec- ~, i.v. 10~kaM,j sec-1, i.v. lOakaM2J sec-1, i.v. Va!~,~liters, i.v. Vr~,k liters, i.v. (CI~),,,,' ml/min, i.v. (Cl~)m,t," ml/min, i.v. (CI~),,~," ml/min, i.v. (p.o.) Absorption lag timefl min, p.o. 103k6x.B,p see- 1, p.o. 10aka~.Bfl sec-~, p.o. lOSkoi,M~fl sec- l, p.o.
= IOZ(M2)~/D ;a i.v. (p.o.)
(Ups)|
291 (246) 0.83 (0.65) 6.35 (4.47) 0.33 (0.22) 0.26 (0.18) 0.12 (0.09) 0.14 (0.10) 71 (81) 63 (71) 161 (137) 130 (109) 166(135) 18 (10) 0.43 (0.21) 0.13 0.03
23.9 (20.5)
27.7 19.7 (46.1) 0.23 0.18 (0.26) 0.18 (0.14) 10.8 8.7 (8.2) 1.20 1.08 (1.31) 8.3 (10.3) 55.2 (43.8) 20.9 (35.7)
a,~ hr- 1, i.v. : graphical Computer: analog (digital) fl,~ hr- 1, i.v., plasma : graphical Computer: analog (digital) fl,a h r - l , urine; i.v. (p.o.): graphical A,~ % of dose/liter, i.v. : graphical Computer: analog (digital) Bfl % of dose/liter, i.v. : graphical Computer: analog (digital) V~,b liters, i.v, : graphical (analog) I02(UDe)~/D; c i.v. (p.o.) I 0 2 ( U u , ) j D ;c i.v. (p.o.)
102[D -
49.3 (157.5)
233 (235) 0.76 (0.68) 6.58 (5.77) 0.27 (0.26) 0.18 (0.15) 0.13 (0.11) 0.05 (0.05) 84 (91) 75 (81) 142 (148) 91 (88) 160(107) 15 (10) 0.55 (0.32) 0.19 0.04
10.2 (23.7)
27.7 24.6 (26.5) 0.16 0.15 (0.17) 0.14 (0.15) 10.5 9.5 (8.2) 1.00 0.99 (1.02) 8.7 (9.5) 60.8 (41.9) 29.0 (34.4)
235 (198) 0.82 (0.60) 8.58 (5.22) 0.28 (0.20) 0.27 (0.18) 0.14 (0.10) 0.13 (0.09) 84 (83) 76 (75) 119 (105) 115 (93) 111(152) 9 (8) 0.26 (0.17) 0.16 0.03
22.4 (31.6)
35.6 22.2 (31.7) 0.16 0.14 (0.17) 0.14 (0.15) 12.8 10.6 (12.8) 1.09 1.07 (1.13) 7.2 (8.6) 50.9 (36.2) 26.7 (32.2)
51.6 (157.1)
1.72
239 (231) 0.87 (0.61) 7.61 (5.13) 0.19 (0.21) 0.20 (0.21) 0.12 (0.13) 0.08 (0.08) 86 (87) 76 (78) 114 (116) 124 (115) 135(179) 9 (0) 0.41 (0.32) 0.22 0.07
19.9 (27.6)
27.7 22.0 (28.6) 0.16 0.15 (0.20) 0.15 (0.16) 8.8 9.8 (9.0) 0.95 1.02 (1.09) 10.2 (9.2) 48.0 (37.4) 32.1 (34.8)
92.3 (302.3)
B (64.1, 16.7)
234 (186) 0.45 (0.56) 6.39 (4.28) 0.27 (0.17) 0.25 (0.15) 0.11 (0.06) 0.14 (0.09) 116 (83) 108 (73) 121 (99) 112 (87) 87(85) 27 (27) 0.11 (0.14) 0.16 0.01
27.2 (26.2)
24.9 18.5 (23.4) 0.12 0.13 (0.13) 0.12 (0.1 I) 12.0 9.4 (10.1) 1.08 1.08 (1.18) 7.6 (9.5) 51.9 (48.4) 20.9 (25.4)
66.7 (191.7)
237 (211) 0.82 (0.68) 6.57 (5.47) 0.18 (0.16) 0.21 (0.18) 0.08 (0.07) 0.15 (0.11) 91 (95) 80 (85) 110 (101) 87 (99) 93(73) 15 (8) 0.15 (0.07) 0.10 0.01
32.7 (19.7)
27.7 23.2 (13.6) 0.15 0.13 (0.13) 0.12 (0.10) 9.0 8.6 (3.6) 0.99 0.95 (0.91) 10.1 (10.5) 46.4 (51.0) 20.9 (29.3)
125.7 (354.6)
2.04
C (79.7, 187)
Parameters for Disopyramide Pharmacokinetics
95.5 (298.0)
1.77
Surface area, m 2 :
D, dose, mg: i.v. (p.o.):
A (65.3, 173)
I.
Subject (kg, era):
Table
245 + 23 (218 _+ 23) 0.76 + 0.16(0.63 +- 0.05) 7.00 + 0.91 (5.06 +- 0.58) 0.25 + 0.06 (0.20 +- 0.04) 0.23 + 0.04(0.18 +- 0.02) 0.12 _+ 0.02 (0.09 +- 0.03) 0.12 + 0.04 (0.09 • 0.02) 89 +- 15 (87 + 5) 80_+ 15(77 + 5 ) 129 + 20(118 +_ 20) 111 + 18(99_+ 11) 125 ,+ 34(122 + 41) 1 6 + 7 ( 1 1 +_9) 0.32 +_ 0.18 (0.21 + 0.10) 0.16 +- 0.04 0.03 + 0.02
22.7 + 7.6 (24.9 + 4.5)
28.6 +_ 3.6 21.7 +- 2.3 0.16 + 0.04 0.15 + 0.02 0.14 +_ 0.02(0.14 + 0.02) 10.7 +- 1.6 9.4 _+ 0.7 1.05 _+ 0.09 1.03 + 0.05 8.7 + 1.3 (9.6 + 0.7) 52.2 +- 5.2 (43.1 +- 5.9) 25.1 + 4.9 (32.0 +- 4.0)
Average +- SD
el.
t~
B
D M2
unchanged and monodealkylated disopyramide, respectively. The parenthetical values are based on the kn~ values obtained by analog computer fitting. ~This overall steady-state volume of distribution was calculated from V~(ksr + krn)/krn since V~/V~ = krn/(ksr + krn), where the knr and kra values were obtained graphically. The parenthetical values are from analog computer obtained constants. The psendo-steady-state volumes of distribution calculated from (Clp)tot/fl averaged 80 +_ 4 and 95 _+ 12 for two different graphical estimates of(Cl~)to . and 89 _+ 6 for the analog computer obtained (Cl~)to~and were consistent with the steady-state volumes.
B
and they were calculated from kas~, = (UM,)~kB~/[D ~ (Un~)0o] and kn~ = = kau - kn~,, where (Una)~ and (U~,)~ are the total amounts of drug renally excreted as
M~ ~
,
