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Propafenone kinetics in the horse
Propafenone Kinetics in the Horse Comparative Analysis of Compartmental NoncompartrViental Models
ANNA PUIGDEMONT,
and
JOSEPLLUISRIU, RAIMONGUITART,AND MARGARITA ARBOIX
The propafenone kinetics after intravenous (i.v.) administration have been studied in the horse by a comparative analysis of compartmental and noncompartmental models. The pharmacokinetic parameters showed a large distribution (Vdss = 1021 + 211 L) and a high clearance (Cl = 7019 + 1746 mL/min) of the drug. The plasma concentrations were very low, under 1 kg/mL, in most cases; after 30 min these concentrations can be considered as nonefficient for the treatment of arrhythmia. There were no significant differences between pharmacokinetic parameters found with the use of compartmental and noncompartmental models. Key Words: Compartmental its; Horse; Propafenone
and noncompartmental
models;
Pharmacokinet-
INTRODUCTION Propafenone is a Class I antiarrhythmic agent, with a weak P-adrenoceptor antagonist activity, and to a lesser extent Class IIIand IV activity (McLeod et al., 1984). It has effectiveness in some patients unresponsive to other conventional antiarrhythmic drugs therapy. Several studies conducted on limited numbers of human patients have shown that propafenone is either more or as efficient as flecainide, mexiletine, lignocaine, quinidine, disopyramide, metoprolol, and amiodarone for prevention and suppression of supraventricular and ventricular arrhythmias (Klempt et al., 1982; Rehnquist et al., 1984; Dinh et al., 1985; Korsukewitz et al., 1985; Fauchier et al., 1986). Clinical studies in human patients found that propafenone can be used in different types of arrhythmias: ventricular, supraventricular, and also in arrhythmia associated with Wolff-Parkinson-White syndrome. Most clinical studies have been conducted on human patients; however, many preliminary experimental studies performed on dogs (Karagueuzian et al., 1982a, 1982b; Von Philipsborn et al., 1984) have shown a clear influence of propafenone on the contractility of vascular smooth muscle of canine coronary arteries (Harden and Bellardinelli, 1980; Scholz, 1983), as well as its ability in reducing cardiac output and ventricular systolic pressure From the Departament de Farmacologia, Facultat de Veterinaria, Universitat Autbnoma de Barcelona, Bellaterra, Barcelona, Spain. Address reprint requests to: Dr. M. Arboix, Departament de Farmacologia, Facultat de Veterinaria, Universitat Autbnoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Received November, 1988; revised and accepted June, 1989. 79 Journalof
Pharmacological Methods
Q 1990 Elsevier Science Publishing
23, 79-85 WXXI) Co., Inc., 655 Avenue of the Americas,
New York, NY 10010
80
A. Puigdemont
et al.
(Karagueuzian et al., 1984), and for suppressing tachycardia (Karagueuzian et al., 1982a). Its efficiency as an antiarrhythmic drug has been tested in several other animal species (Scholz, 1983; Karagueuzian et al., 1982a, 198213; Katoh et al., 1982). Pharmacokinetic data have shown that propafenone is a drug with a relatively short tlIZ, and a large interindividual variability (Connolly et al., 1983; Salerno et al., 1984; Arboix et al., 1985), which might be related to the polymorphism of its metabolism (Siddoway et al., 1987). In the compartmental analysis of plasma level curves, a large variability between individuals of the same age, gender, or weight has also been described. Whereas some of these curves fitted a monocompartmental model, in other cases a bicompartmental model was more suitable (Connolly et al., 1984). This high variability and the short duration of the drug distribution phase in most animals have suggested the need for trying a noncompartmental model in the analysis of the plasma level of propafenone in horses, the subject of our study, and then comparing the resulting kinetic parameters to those of compartmental analysis. MATERIALS AND METHODS Experimental
Protocol
After 12 h of fasting, seven Arabian male horses were treated with an intravenous (i.v.) dose of 2 mg/kg of propafenone. Blood samples were withdrawn fom the jugular vein at the following times after drug administration: 5, 10, 20, 30, 45, 60, 90,120,150,180, 210, and 240 min. Plasma was then separated and stored at -20°C until analysis. Propafenone was determined in plasma using the HPLC technique described by Harapat and Kates (1982). Data Analysis Two methods were used for the analysis of plasma level curves: 1. Noncompartmental 2. Multicompartmental
analysis based on statistical moment theory. analysis, based on nonlinear regression iterative programs.
Statistical Moments The time course of drug concentration in plasma can be viewed as a statistical distribution curve, where the mean residence time of the drug in the body is MRT AUC;
=
and the variance of the mean residence time is VRT. AUC, MRT, and VRT are, respectively, the zero, first, and second moment of the drug plasma concentrationtime curve (Yamaoka et al., 1978; Brockmeier and Von Hattingberg, 1986). The moments defined by these equations can be calculated by numeric integration using the trapezoidal formula from the changes of plasma concentration with
Propafenone
Kinetics in the Horse
time. Because the C is observed in a limited period of time, the extrapolation to infinite time using a monoexponential (a*empf) equation is needed to estimate the statistical moments. The MRT of a drug that requires multicompartmental characterization is a function of the model rate constants for elimination and transfer of drug between peripheral and central compartments (Yamaoka et al., 1978). However, in noncompartmental terms the following relationship is useful: MRT = ; where K is a first-order rate constant equal to the ratio of clearance to apparent volume of distribution at steady state. It is appropriate to consider the product of 0.693 and MRT as the “effective” half-life of a drug requiring a multicompartmental model. The mean residence time enables calculation of the apparent volume of distribution at steady state independent of compartmental analysis using the following equation (Benet and Galeazzi, 1979): Vd,,
= Cl MRT
Multicompartmental Kinetic Analysis The plasma concentration-time relationship was fitted, using the PCNONLIN program (Metzler and Weiner, 1986) to obtain the pharmacokinetic parameters, to the equation : C, = A e-“’
+ B e-@
where C, is the propafenone concentration in plasma at time t, A is the intercept of distribution slope with the ordinate, and B is the intercept of the back extrapolated monoexponential elimination slope with the ordinate. Statistical
Analysis
The pharmacokinetic parameters determined by noncompartmental partmental models were compared using the Student’s t test.
and com-
RESULTS
Table 1 shows the plasma concentration values of propafenone obtained at various time-points after administration of 2 mg/kg of propafenone to seven male horses. The plasma concentrations were in most instances below 1 kg/mL. Figure 1 shows the plot against time of the mean plasma concentrations of propafenone in the seven horses. Data were fitted using a nonlinear regression iterative program, following a two-compartment open model system. The variations are quite large in the first phase of the curve. The curve shows that propafenone has a fast distribution in the body during the first min after its i.v. administration and a slower decline 30 min thereafter. Table 2 shows the results of the statistical moments, and pharmacokinetic parameters computed according to the statistical moments theory, as mentioned in the
81
TABLE 1 Plasma Concentrations After 2 mg/kg i.v. Administration
of Propafenone
in 7 Horses
PLASMACONCENTRATIONS
TIME
(min)
(ng/mL)
HORSE
#I
#2
#3
#4
#5
#6
5 10 20 30 45 60 90 120 150 180 210 240
858 754 672 446 419 384 328 299 205 185 140
1452 1103 953 738 732 588 507 329 315 302 207 -
1272 1178 1074 649 601 481 390 370 328 275
1128 929 859 739 658 559 424 409 333 215 225 179
798 639 519 456 296 260 251 195 164 134 149 131
987 588 492 454 38.5 350 238 193 178 182 709 118
#7 1070 947 857 720 543 451 318 254 161 115 80 69
Z + SD 1049 890 790 696 511 468 389 313 263 222 183 152
+ " t f f f 2 + f + + +
233 248 246 230 168 139 134 108 93 96 82 70
time (mid FIGURE 1. Plot of the time-course of the mean plasma concentrations in seven male horses after administration of 2 mg/kg of propafenone. The constant estimates by PCNONLIN program from this plot are: OL= 0.052 min-’ and p = 0.0059 min -‘.
Propafenone
Kinetics in the Horse
TABLE 2 Pharmacokinetic Parameters Obtained by Noncompartmental Analysis in 7 Male Horses After 2 mg/kg i.v. Administration of Propafenone HORSE# PARAMETER
W (kg) MRT AUC;
(kg min/mL)
tlnp (min) p (min-') Vde (L) Vd,, (L) Cl (mUmin)
1
2
3
4
5
6
7
403 152 109 110 0.0063 1175 1125 7422
404 133 139 97 0.0071 813 772 5802
455 207 205 161 0.0043 1032 921 4443
420 148 134 105 0.0066 956 927 6282
320 187 86 133 0.0052 1429 1390 7454
325 148 83 103 0.0067 1156 1145 7760
430 87 86 64 0.0109 914 867 9973
Methods section, for the plasma level curves of the seven horses studied. The tlnp ranges between I’/ and 2 hr (110 +- 30 min), except for horse #7, which has a tlnp of only 1 hr. Accordingly, the clearance averages 7019 t 1746 mUmin, with the highest value corresponding to horse #7 (9973 mUmin). Mention must also be made of the high distribution volumes found Wd,, = 1021 + 211 L). The pharmacokinetic parameters estimated by compartmental analysis based on nonlinear regression are shown in Table 3. Values obtained for the various parameters are similar to their counterparts presented in Table 2. There were no statistically significant differences between the values found by compartmental (Table 3) and noncompartmental (Table 2) analyses (p < 0.01). DISCUSSION
The results of this study show that propafenone has a fast distribution in the body after i.v. administration. Figure I shows that the distribution phase has a high slope value of monoexponential distribution time (a = 0.052 min-‘). Keller et al. (1978), Connolly et al. (1983), and Fabretti et al. (1986) in humans,
TABLE 3 Pharmacokinetic Parameters Obtained by Multicompartmental Analysis of Propafenone in 7 Horses After 2 mg/kg i.v. Administration of Propafenone HORSE # PARAMETER AUC; (pg minlml) tlf.2p (min) a (min-') p (min-') Vdp (L) Vdss (L) Cl (mUmin)
1
2
3
4
5
6
7
116 130 0.061 0.0053 1310 1236 6944
138 93 0.029 0.0075 777 743 5830
221 197 0.024 0.0035 1178 1001 4122
132 102 0.046 0.0068 938 940 6381
96 195 0.046 0.0036 1858 1637 6690
80 93 0.32 0.0075 1068 977 8006
86 71 0.051 0.0098 1016 894 9954
83
84
A. Puigdemont
et al.
and Karagueuzian et al. (1982a) in dogs, found that propafenone has no therapeutic value at plasma concentrations lower than 500 ng/mL. The results of the present study indicate that, after 30 min of drug administration to the horse, the propafenone plasma concentration fell down below this limit and, thus, it can be considered as nonefficient for the treatment of arrhythmias. This suggests the convenience of using a continuous infusion administration in order to avoid the problems associated with the rapid decline of drug plasma concentrations seen after a single i.v. dose administration. This conclusion is derived from the high distribution volume and the fast metabolism of propafenone. The low plasma concentrations of this drug agree with results found in studies conducted on other animal species (Connolly et al., 1984; Puigdemont et al., 1987). The estimation of pharmacokinetics parameters obtained using compartmental and noncompartmental models were not significantly different; this indicates that the two compartmental models give a good fit for individual data of drug plasma concentrations after i.v. injection. The MRT takes into account all the phenomena that control the life of a drug in the organism, characterized by the curve of the plasma levels. As stated above, its determination is not always noncompartmental and depends on the kinetic constants between compartments (Yamoaka et al., 1978). However, the MRT calculation allows interindividual comparisons and avoids variability in the different half-lifes obtained from bicompartmental analyses, in which both exponentials (Y and p can show, as in the present case (Table 3), a high variability. For these reasons, it can be concluded that the use of noncompartmental analysis methods, based on the statistical moment theory, is adequate for description and comparison of propafenone pharmacokinetics in the horse, which show important interindividual differences.
REFERENCES Arboix M, Puigdemont A, Moya A, Cinca J (1985) Pharmacokinetic intravenous propafenone in patients with episodes of paroxysmal supraventricular tachycardia. Methods Find Exp Clin Pharmacol7:435-438. Benet LZ, Galeazzi RL (1979) Noncompartmental determination of the steady-state volume of distribution. / Pharmacol Sci 68:1071-1074. Brockmeier D, Von Hattingberg HM (1986) Mean residence time. Methods Find Fxp C/in Pharmacot 8:309-312. Connolly SJ, Kates RE, Lebsack CS, Harrison DC, Winkle RA (1983) Clinical pharmacology of propafenone. Circulation 68:589-596. Connolly SJ, Lebsack C, Winkle RA, Kates RE (1984) Propafenone disposition kinetics in arrhythmia patients. C/in Pharmacol Ther 36:163-168.
Dinh H, Murphy ML, Baker BJ, de Soyza N, Franciosa JA (1985) Efficacy of propafenone compared with quinidine in chronic ventricular arrhythmias. Am / Cardiol55:1520-1524. Fabretti L, Marchesini B, Capucci, A, Cavallini C, Cubelli S, Ambrosini E, Magnani B (1986) Antiarrhythmic efficacy of propafenone: Evaluation of effective plasma levels following single and multiple doses. Eur] C/in Pharmaco/30:665-671. Fauchier JP, Cosnay P, Rouesnel P, Moquet B, Huguet R (1986) Etude comparative de I’efficacite de la propafenone et de I’amiodarone dans le traitement des extrasystoles ventriculaires chroniques. Arch Ma/ad Coeur Vaiss 79:1495-1505. Harapat SR, Kates RE (1982) High performance liquid chromatographic analysis of propafenone in human plasma samples. ] Chromatogr 230:448453.
Propafenone Harden DR, Bellardinelli L (1980) Effects of propafenone on TEA-induced action potentials in vascular smooth muscle of canine coronary arteries. Experientia 36:1082-1083. Karagueuzian HS, Fujimoto T, Katoh T, Peter T, McCullen A, Mandel WJ (1982a) Suppression of ventricular arrhythmias by propafenone, a new antiarrhythmic agent, during acute myocardial infarction in the conscious dog. A comparative study with lidocaine. Circulation 66:1190-1198. Karagueuzian HS, Katoh T, McCullen A, Mandel WJ, Peter T (1984) Electrophysiologic and hemodynamic effects of propafenone, a new antiarrhythmic agent on the anesthetized closedchest dog: Comparative study with lidocaine. Am Heart/ 107:418-424. Karagueuzian HS, Katoh T, Sugi K, McCullen A, Mandel WJ, Peter T (1982b) Electrophysiologic effects of propafenone, a new antiarrhythmic drug, on isolated cardiac tissue. Circulation (suppl II) 66: II-378 (abst). Katoh T, Karagueuzian HS, Peter T, Sugi K, McCullen A, Mandel WJ (1982) Comparative effects of antiarrhythmic drugs on canine idioventricular pacemakers. In vivo and in vitro correlation. jpn Heart / (suppl) 23:87-89.
Kinetics in the Horse
stration of beta-adrenoceptor blockade by propafenone hydrochloride: clinical pharmacologic and adenylate cyclase activation studies. / Pharmacol Exp Ther 228:461-466. Metzler CM, Weiner DL (1986) PCNONLIN. ington: Statistical Consultants, Inc.
Lex-
Puigdemont A, Lligona LL, Arboix M, de Mora F, Ferndndez J (1987) Pharmacokinetics of propafenone in the dog after single-dose intravenous administration. / vet Pharmacol Therap 10:351353. Rehnquist N, Ericsson CC, Eriksson S, Olsson G, Svensson G (1984) Comparative investigation of the anti-arrhythmic effects of propafenone (Rytmonorm) and lisocaine in patients with ventricular arrhythmias during acute myocardial infarction. Acta Med Stand 216:525-530. Salerno DM, Cranrud C, Sharkey P, Asinger R, Hodges M (1984) A controlled trial of propafenonefortreatmentoffrequentand repetitiveventricular premature complexes. Am / Cardiol 53 : 77-83. Scholz H (1983) The pharmacology of propafenone. In Cardiac Arrhythmias: Diagnosis, Prognosis, and Therapy. Eds., M Schlepper and B Olsson. Berlin: Springer-Verlag, pp. 103-111.
Keller K, Meyer-Estorf G, Beck OA, Hochrein H (1978) Correlation between serum concentration and pharmacologic effect on atrioventricular conduction time of antiarrhythmic drug propafenone. Eur J Clin Pharmacol 13:17-20.
Siddoway LA, Thompson KA, McAllister CB, Wang T, Wilkinson GR, Roden DM, Woosley RL (1987) Polymorphism of propafenone metabolism and disposition in man: Clinical and pharmacokinetic consequences. Circulation 75:785-791.
Klempt HW, Nayebagha A, Fabry E (1982) Antiarrhythmic efficacy of mexiletine, propafenone and flecainide in ventricular premature beats: a comparative study in patients after myocardial infarction (translation). Z Kardiol 71:340-349.
Von Philipsborn G, Cries J, Hoffman HP, Kreiskott H, Kretzschmar R, Muller CD, Raschack M, Teschendorf HJ (1984) Pharmacological studies with propafenone and its main metabolite 5-hydroxypropafenone. Arzneim-Forsch-Drug Res 34:1489-1497.
Korsukewitz J, Wegscheider K, Schmutzler H (1985) ldiopathische ventrikulare Tachyarrhythmien. Deut Med Wochenschr 110:1103-1107. McLeod AA, Stiles CL, Shand DC (1984) Demon-
Yamaoka K, Nakagawa T, Uno T (1978) Statistical moments in pharmacokinetics. / Pharmacokinet Biopharm 6:547-558.
85
ANNA PUIGDEMONT,
and
JOSEPLLUISRIU, RAIMONGUITART,AND MARGARITA ARBOIX
The propafenone kinetics after intravenous (i.v.) administration have been studied in the horse by a comparative analysis of compartmental and noncompartmental models. The pharmacokinetic parameters showed a large distribution (Vdss = 1021 + 211 L) and a high clearance (Cl = 7019 + 1746 mL/min) of the drug. The plasma concentrations were very low, under 1 kg/mL, in most cases; after 30 min these concentrations can be considered as nonefficient for the treatment of arrhythmia. There were no significant differences between pharmacokinetic parameters found with the use of compartmental and noncompartmental models. Key Words: Compartmental its; Horse; Propafenone
and noncompartmental
models;
Pharmacokinet-
INTRODUCTION Propafenone is a Class I antiarrhythmic agent, with a weak P-adrenoceptor antagonist activity, and to a lesser extent Class IIIand IV activity (McLeod et al., 1984). It has effectiveness in some patients unresponsive to other conventional antiarrhythmic drugs therapy. Several studies conducted on limited numbers of human patients have shown that propafenone is either more or as efficient as flecainide, mexiletine, lignocaine, quinidine, disopyramide, metoprolol, and amiodarone for prevention and suppression of supraventricular and ventricular arrhythmias (Klempt et al., 1982; Rehnquist et al., 1984; Dinh et al., 1985; Korsukewitz et al., 1985; Fauchier et al., 1986). Clinical studies in human patients found that propafenone can be used in different types of arrhythmias: ventricular, supraventricular, and also in arrhythmia associated with Wolff-Parkinson-White syndrome. Most clinical studies have been conducted on human patients; however, many preliminary experimental studies performed on dogs (Karagueuzian et al., 1982a, 1982b; Von Philipsborn et al., 1984) have shown a clear influence of propafenone on the contractility of vascular smooth muscle of canine coronary arteries (Harden and Bellardinelli, 1980; Scholz, 1983), as well as its ability in reducing cardiac output and ventricular systolic pressure From the Departament de Farmacologia, Facultat de Veterinaria, Universitat Autbnoma de Barcelona, Bellaterra, Barcelona, Spain. Address reprint requests to: Dr. M. Arboix, Departament de Farmacologia, Facultat de Veterinaria, Universitat Autbnoma de Barcelona, 08193 Bellaterra, Barcelona, Spain. Received November, 1988; revised and accepted June, 1989. 79 Journalof
Pharmacological Methods
Q 1990 Elsevier Science Publishing
23, 79-85 WXXI) Co., Inc., 655 Avenue of the Americas,
New York, NY 10010
80
A. Puigdemont
et al.
(Karagueuzian et al., 1984), and for suppressing tachycardia (Karagueuzian et al., 1982a). Its efficiency as an antiarrhythmic drug has been tested in several other animal species (Scholz, 1983; Karagueuzian et al., 1982a, 198213; Katoh et al., 1982). Pharmacokinetic data have shown that propafenone is a drug with a relatively short tlIZ, and a large interindividual variability (Connolly et al., 1983; Salerno et al., 1984; Arboix et al., 1985), which might be related to the polymorphism of its metabolism (Siddoway et al., 1987). In the compartmental analysis of plasma level curves, a large variability between individuals of the same age, gender, or weight has also been described. Whereas some of these curves fitted a monocompartmental model, in other cases a bicompartmental model was more suitable (Connolly et al., 1984). This high variability and the short duration of the drug distribution phase in most animals have suggested the need for trying a noncompartmental model in the analysis of the plasma level of propafenone in horses, the subject of our study, and then comparing the resulting kinetic parameters to those of compartmental analysis. MATERIALS AND METHODS Experimental
Protocol
After 12 h of fasting, seven Arabian male horses were treated with an intravenous (i.v.) dose of 2 mg/kg of propafenone. Blood samples were withdrawn fom the jugular vein at the following times after drug administration: 5, 10, 20, 30, 45, 60, 90,120,150,180, 210, and 240 min. Plasma was then separated and stored at -20°C until analysis. Propafenone was determined in plasma using the HPLC technique described by Harapat and Kates (1982). Data Analysis Two methods were used for the analysis of plasma level curves: 1. Noncompartmental 2. Multicompartmental
analysis based on statistical moment theory. analysis, based on nonlinear regression iterative programs.
Statistical Moments The time course of drug concentration in plasma can be viewed as a statistical distribution curve, where the mean residence time of the drug in the body is MRT AUC;
=
and the variance of the mean residence time is VRT. AUC, MRT, and VRT are, respectively, the zero, first, and second moment of the drug plasma concentrationtime curve (Yamaoka et al., 1978; Brockmeier and Von Hattingberg, 1986). The moments defined by these equations can be calculated by numeric integration using the trapezoidal formula from the changes of plasma concentration with
Propafenone
Kinetics in the Horse
time. Because the C is observed in a limited period of time, the extrapolation to infinite time using a monoexponential (a*empf) equation is needed to estimate the statistical moments. The MRT of a drug that requires multicompartmental characterization is a function of the model rate constants for elimination and transfer of drug between peripheral and central compartments (Yamaoka et al., 1978). However, in noncompartmental terms the following relationship is useful: MRT = ; where K is a first-order rate constant equal to the ratio of clearance to apparent volume of distribution at steady state. It is appropriate to consider the product of 0.693 and MRT as the “effective” half-life of a drug requiring a multicompartmental model. The mean residence time enables calculation of the apparent volume of distribution at steady state independent of compartmental analysis using the following equation (Benet and Galeazzi, 1979): Vd,,
= Cl MRT
Multicompartmental Kinetic Analysis The plasma concentration-time relationship was fitted, using the PCNONLIN program (Metzler and Weiner, 1986) to obtain the pharmacokinetic parameters, to the equation : C, = A e-“’
+ B e-@
where C, is the propafenone concentration in plasma at time t, A is the intercept of distribution slope with the ordinate, and B is the intercept of the back extrapolated monoexponential elimination slope with the ordinate. Statistical
Analysis
The pharmacokinetic parameters determined by noncompartmental partmental models were compared using the Student’s t test.
and com-
RESULTS
Table 1 shows the plasma concentration values of propafenone obtained at various time-points after administration of 2 mg/kg of propafenone to seven male horses. The plasma concentrations were in most instances below 1 kg/mL. Figure 1 shows the plot against time of the mean plasma concentrations of propafenone in the seven horses. Data were fitted using a nonlinear regression iterative program, following a two-compartment open model system. The variations are quite large in the first phase of the curve. The curve shows that propafenone has a fast distribution in the body during the first min after its i.v. administration and a slower decline 30 min thereafter. Table 2 shows the results of the statistical moments, and pharmacokinetic parameters computed according to the statistical moments theory, as mentioned in the
81
TABLE 1 Plasma Concentrations After 2 mg/kg i.v. Administration
of Propafenone
in 7 Horses
PLASMACONCENTRATIONS
TIME
(min)
(ng/mL)
HORSE
#I
#2
#3
#4
#5
#6
5 10 20 30 45 60 90 120 150 180 210 240
858 754 672 446 419 384 328 299 205 185 140
1452 1103 953 738 732 588 507 329 315 302 207 -
1272 1178 1074 649 601 481 390 370 328 275
1128 929 859 739 658 559 424 409 333 215 225 179
798 639 519 456 296 260 251 195 164 134 149 131
987 588 492 454 38.5 350 238 193 178 182 709 118
#7 1070 947 857 720 543 451 318 254 161 115 80 69
Z + SD 1049 890 790 696 511 468 389 313 263 222 183 152
+ " t f f f 2 + f + + +
233 248 246 230 168 139 134 108 93 96 82 70
time (mid FIGURE 1. Plot of the time-course of the mean plasma concentrations in seven male horses after administration of 2 mg/kg of propafenone. The constant estimates by PCNONLIN program from this plot are: OL= 0.052 min-’ and p = 0.0059 min -‘.
Propafenone
Kinetics in the Horse
TABLE 2 Pharmacokinetic Parameters Obtained by Noncompartmental Analysis in 7 Male Horses After 2 mg/kg i.v. Administration of Propafenone HORSE# PARAMETER
W (kg) MRT AUC;
(kg min/mL)
tlnp (min) p (min-') Vde (L) Vd,, (L) Cl (mUmin)
1
2
3
4
5
6
7
403 152 109 110 0.0063 1175 1125 7422
404 133 139 97 0.0071 813 772 5802
455 207 205 161 0.0043 1032 921 4443
420 148 134 105 0.0066 956 927 6282
320 187 86 133 0.0052 1429 1390 7454
325 148 83 103 0.0067 1156 1145 7760
430 87 86 64 0.0109 914 867 9973
Methods section, for the plasma level curves of the seven horses studied. The tlnp ranges between I’/ and 2 hr (110 +- 30 min), except for horse #7, which has a tlnp of only 1 hr. Accordingly, the clearance averages 7019 t 1746 mUmin, with the highest value corresponding to horse #7 (9973 mUmin). Mention must also be made of the high distribution volumes found Wd,, = 1021 + 211 L). The pharmacokinetic parameters estimated by compartmental analysis based on nonlinear regression are shown in Table 3. Values obtained for the various parameters are similar to their counterparts presented in Table 2. There were no statistically significant differences between the values found by compartmental (Table 3) and noncompartmental (Table 2) analyses (p < 0.01). DISCUSSION
The results of this study show that propafenone has a fast distribution in the body after i.v. administration. Figure I shows that the distribution phase has a high slope value of monoexponential distribution time (a = 0.052 min-‘). Keller et al. (1978), Connolly et al. (1983), and Fabretti et al. (1986) in humans,
TABLE 3 Pharmacokinetic Parameters Obtained by Multicompartmental Analysis of Propafenone in 7 Horses After 2 mg/kg i.v. Administration of Propafenone HORSE # PARAMETER AUC; (pg minlml) tlf.2p (min) a (min-') p (min-') Vdp (L) Vdss (L) Cl (mUmin)
1
2
3
4
5
6
7
116 130 0.061 0.0053 1310 1236 6944
138 93 0.029 0.0075 777 743 5830
221 197 0.024 0.0035 1178 1001 4122
132 102 0.046 0.0068 938 940 6381
96 195 0.046 0.0036 1858 1637 6690
80 93 0.32 0.0075 1068 977 8006
86 71 0.051 0.0098 1016 894 9954
83
84
A. Puigdemont
et al.
and Karagueuzian et al. (1982a) in dogs, found that propafenone has no therapeutic value at plasma concentrations lower than 500 ng/mL. The results of the present study indicate that, after 30 min of drug administration to the horse, the propafenone plasma concentration fell down below this limit and, thus, it can be considered as nonefficient for the treatment of arrhythmias. This suggests the convenience of using a continuous infusion administration in order to avoid the problems associated with the rapid decline of drug plasma concentrations seen after a single i.v. dose administration. This conclusion is derived from the high distribution volume and the fast metabolism of propafenone. The low plasma concentrations of this drug agree with results found in studies conducted on other animal species (Connolly et al., 1984; Puigdemont et al., 1987). The estimation of pharmacokinetics parameters obtained using compartmental and noncompartmental models were not significantly different; this indicates that the two compartmental models give a good fit for individual data of drug plasma concentrations after i.v. injection. The MRT takes into account all the phenomena that control the life of a drug in the organism, characterized by the curve of the plasma levels. As stated above, its determination is not always noncompartmental and depends on the kinetic constants between compartments (Yamoaka et al., 1978). However, the MRT calculation allows interindividual comparisons and avoids variability in the different half-lifes obtained from bicompartmental analyses, in which both exponentials (Y and p can show, as in the present case (Table 3), a high variability. For these reasons, it can be concluded that the use of noncompartmental analysis methods, based on the statistical moment theory, is adequate for description and comparison of propafenone pharmacokinetics in the horse, which show important interindividual differences.
REFERENCES Arboix M, Puigdemont A, Moya A, Cinca J (1985) Pharmacokinetic intravenous propafenone in patients with episodes of paroxysmal supraventricular tachycardia. Methods Find Exp Clin Pharmacol7:435-438. Benet LZ, Galeazzi RL (1979) Noncompartmental determination of the steady-state volume of distribution. / Pharmacol Sci 68:1071-1074. Brockmeier D, Von Hattingberg HM (1986) Mean residence time. Methods Find Fxp C/in Pharmacot 8:309-312. Connolly SJ, Kates RE, Lebsack CS, Harrison DC, Winkle RA (1983) Clinical pharmacology of propafenone. Circulation 68:589-596. Connolly SJ, Lebsack C, Winkle RA, Kates RE (1984) Propafenone disposition kinetics in arrhythmia patients. C/in Pharmacol Ther 36:163-168.
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