Comparative pharmacodynamics of betamethyl digoxin and digoxin in man The positive inotropic effects and serum glycoside levels following intravenous and oral administration of betamethyl digoxin (BMD) were measured and compared with those of digoxin in normal adults. The cardiac inotropy was assessed noninvasively in the abbreviation of the electromechanical systolic index (QS2/) obtained by serial measurements of systolic time intervals. Following 0.8 mg BMD intravenously, the QS2/ abbreviation occurred within 3 min and reached a maximum at 4 hr. The time-course and the magnitude of the response were essentially the same as those obtained with 0.8 mg digoxin given intravenously in the same subjects. The serum glycoside levels were also similar for both drugs. When administered orally the QS2/ abbreviation to 0.8 mg BMD appeared at 40 min and reached a maximum at 4 hr. The time-course and the magnitude of the effects were similar to those observed following oral digoxin. The blood digitalis levels following the drug ingestion, however, were significantly higher for BMD than for digoxin which suggests greater gastrointestinal absorption of BMD. Based on our observations, the inotropic effects of BMD are similar to those of digoxin. Our results, however, do not demonstrate greater cardiac activity after oral administration of BMD despite higher blood levels.
Gopal Das, M.D., Frederick N. Talmers, M.D., and Arnold M. Weissler, M.D. Allen Park and Detroit, Mich. Cardiology Section, Department of Medicine, Veterans Administration Hospital, and Wayne State University, School of Medicine
In previous studies 5 , 8, 9 enhanced and more complete gastrointestinal absorption of tritiumlabeled betamethyl digoxin (BMD) (a methyl derivative of digoxin) have been reported. Based on these studies, it was anticipated that the BMD given orally would result in a more rapid onset of action and greater cardiac effects than digoxin, an effect long desired in drugs Supported by a research grant from G. D. Searle & Co. Received for publication Feb. 7, 1977. Accepted for publication May 5, 1977. Reprint requests to: Gopal Das, F.A.C.C., Director, Cardiac Laboratories, Veterans Administration Hospital, Allen Park, Mich. 48101.
280
used in the treatment of congestive heart failure. Failure to find a systematic comparison of cardiac properties of the two drugs in the literature led us to evaluate and compare the positive inotropic properties of BMD and digoxin in man. The systolic time interval response to digitalis glycoside offers a convenient noninvasive method of studying serial changes in the left ventricular inotropic response to these drugs. This method lends itself to comparison of the cardiac responses to the various glycosides over prolonged study periods and hence provides the opportunity to test the hypothe-
Betamethyl digoxin and digoxin
Volume 22 Number 3
sis that increased absorption results in greater cardiac response to BMD than to digoxin. The positive inotropic effects and the serum glycoside levels following intravenous and oral administration of BMD were measured and compared with those of digoxin in normal adult volunteers. The cardiac inotropy was assessed noninvasively in the abbreviation of the electromechanical systolic time index (QS2I) obtained in serial measurements of systolic time intervals.
o
-30
I
3m
I
5m
--e--
BMD (I.V.)
-0-
Digoxin (IV)
I
10
I
20
I
I
40 Ih
I
2
I
I
4 6
281
I
24h
Time
Materials and methods
Studies were performed on 5 healthy volunteers aged 22 to 34. In none were cardiac abnormalities detected by a complete physical examination, chest roentgenographic and electrocardiographic examinations. Each subject received 0.8 mg BMD intravenously, 0.8 mg digoxin intravenously, 0.8 mg BMD orally, and 0.75 mg digoxin orally at 4- to 6-wk intervals. The drugs were selected at random and were administered in a single dose. The cardiac responses for each regimen were measured by the noninvasive technique of systolic time intervalS. 13 The subjects were studied in the postabsorptive state. Starting at 8:00 A.M., an indwelling catheter was placed in a vein in the left arm and was used to collect blood samples for digitalis assay. Blood samples were collected immediately following each systolic time interval recording. The serum glycoside activity was measured by the radioimmunoassay technique with the use of Schwartz-Man kit and were expressed as nanograms per milliliter. 10 The two drugs are indistinguishable in the assay by this kit and in our laboratory the technique is insensitive to serum glycoside activity below 0.4 ng/ml. Since digoxin is a significant metabolite of BMD in man, such a conversion will not alter the serum glycoside levels because the test is equally sensitive to both. The systolic time intervals were measured from simultaneous fast speed (100 mm/sec) photographic recordings of an electrocardiographic lead, a phonocardiogram, and a carotid arterial pulse tracing with time markers indicating 40-msec intervals. The phonocardiogram was obtained by use of a contact microphone
Fig. 1. Comparison of positive inotropic responses (QS21 abbreviation, mean ± SEM) to intravenous administration of BMO and digoxin. For each drug onset of action was prompt (within 3 min) and a maximal response occurred at 4 hr following the intravenous administration.
(PSI-Electronics for Medicine) and the carotid arterial pulsations were recorded through a 2.3-cm diameter funnel-shaped pick-up, air coupled to a P23db Statham transducer. Following 30 min of supine rest after the catheter placement, three baseline systolic time interval recordings and blood samples were obtained 10 min apart, and an average of these three observations was used as a control. The BMD or digoxin was administered either in a vein in the right arm or was swallowed with a little water. The systolic time interval recordings and the blood samples were repeated at 3, 5, 10, 20, and 40 min and 1, 2, 4, 6, and 24 hr following the drug administration. The cardiac cycle length (R-R interval), electromechanical systolic time (QS2, measured from the beginning of the QRS complex to the first high-frequency vibration of the second heart sound), and the left ventricular ejection time (L VET, an interval from the beginning to the trough of the incisural notch on the carotid arterial pulse tracing) were measured in 10 consecutive cycles and averaged as described previously.13 The pre-ejection period (PEP) was calculated by subtracting L VET from the QS2' Heart rate was derived by dividing R-R into 60 and was expressed to the nearest integer. The electromechanical systolic time, the left ventricular ejection time, and the pre-ejection period were corrected for the heart rate by means of perviously derived regression equations relating the heart rate and the systolic
282
Das, Talmers, and Weissler
Clinical Pharmacology and Therapeutics
10
--e-- BMD (I.v.) - 0 - Digoxin (IV.)
o .~ 20 o
]
0>
o
Ji'
~
o
Q)
-10
10
-20 _.-.. -.- BMD (P.O.) Digoxin (P.OJ
-0-
Time
Fig. 2. Comparison of serum glycoside levels (mean ± SEM) to intravenous administration of BMO and digoxin.
intervals in normal men and were expressed as electromechanical systolic index (QS21), the left ventricular ejection time index (L VETI) , and pre-ejection period index (PEPI), respectively.6 The abbreviation in these intervals was ploUed against time for each drug. The time constant for the glycoside action following intravenous administration was calculated as described by Forester and co-workers.! Results
Since the molar weights of the two glycosides were so similar (794.94 for BMD and 780.92 for digoxin), correction for this variable was not introduced in the data analysis. The magnitude of maximum QS2I abbreviation in response to both drugs compared with that for L VETI and PEPI was greater and had less variance (QS2I, 23 ± l.9 [SEMj; L VETI, 19 ± 1.9; and PEPI, 10 ± 1.5). Thus the significance of QS2I response was greater than that for LVETI and PEPI (t = 12.3, 10.3, and 7.1, respectively). The comparison of inotropic responses to intravenous administration of BMD and digoxin is shown in Fig. 1. The effect of BMD was apparent within 3 min and gradually increased to a maximum abbreviation of 25 msec at 4 hr. The effect of digoxin was also apparent within 3 min and reached a maximum of 21 msec at 4 hr. The time constants for BMD and digoxin action were 27 and 25 min, respectively. The differences in time course and
-30
~m
5m
It>
26 4b Ih
I
2
I
24h
Time
Fig. 3. Comparison of positive inotropic responses (QS21 abbreviation, mean ± SEM) to oral administration of BMO and digoxin. The onset of action for both drugs was delayed to 40 min and a maximal response occurred at 4 hr following ingestion.
the relative magnitude of the cardiac effects of the two drugs as measured by the time of onset, magnitude of maximum response, time of maximum response, time constant of action, and the area under the response curve were not significant (p > 0.2). The relative magnitude and the time course of the serum glycoside levels following intravenous administration of the two drugs, shown in Fig. 2, were also not different (p > 0.2). The areas under the glycoside curves were 61.7 ± 4.0 (SEM) and 58.5 ± 4.3 (p > 0.4) cm 2 for BMD and digoxin, respectively. Following the oral administration of BMD, the onset of response in QS2I abbreviation appeared at 40 min and reached a maximum of 12 msec at 4 hr (Fig. 3). The time of onset, the magnitude of response, time course of response, and the area under the QS2I curve were not different from those after oral administration of digoxin (p > 0.5). The serum glycoside activity after the oral administration of the two glycosides, however, was different. In 4 of the 5 subjects the glycoside appeared in the blood within 20 min after ingestion of BMD and 40 min (p > 0.2) after digoxin. Thereafter serum levels (Fig. 4) were consistently higher for BMD than those for digoxin up to 6 hr after administration (p
0.5), as illustrated in the lower panel.
greater significance. 14 These findings were confirmed in our study. The abbreviation in the systolic intervals following glycoside administration is unaccompanied by change in the slope of the regression line relating these intervals to heart rate. 14 It has also been documented that the abbreviation in the systolic intervals by glycosides is dose-dependent and closely correlated (r = 0.90) with other independent measures of the left ventricular inotropic responses. 15 These data provide evidence that the systolic interval responses are accurate expres-
284
Das, Talmers, and Weissler
Clinical Pharmacology and Therapeutics
Table I. Comparative pharmacodynamics of betamethyl digoxin and digoxin
Parameter Intravenous administration Onset of QS2I abbreviation Time to maximum response (hr) Time constant of action (min) Magnitude of maximum response (msec, ±SEM) Area under the QS2I response curves (cm2 ± SEM) Peak serum glycoside level (ng/ml, ±SEM) Area under serum glycoside curves (cm2 ±SEM) Oral administration Onset of QS2I abbreviation (min) Time to maximum response (hr) Magnitude of maximum response (msec, ±SEM) Area under the QS2I response curves (cm2' ±SEM) Onset of glycoside appearance in blood (min) Peak serum glycoside level (ng/ml, ±SEM) Area under the serum glycoside curves (cm2, ± SEM)
Betamethyl digoxin (molar weight, 794.94)
Digoxin (molar weight, 780.92)
0.8 mg Immediate (within 3 min) 4 27 25 ± 2.2 70.7 ± 12.7 26.2 ± 3.3 61.7 ± 4.0 0.8 mg 40 4 12 ± 3.1 34.3 ± 8.2 20 3.3 ± 0.68 11.4 ± 2.9
0.8 mg Immediate (within 3 min) 4 25 21 ± 4.0 60.2 ± 9.7 30.1 ± 5.3 58.5 ± 4.3 0.75 mg 40 4 13 ± 3.1 33.4 ± 7.3 40 1.6 ± 0.45 5.0 ± 0.9
Significance NS NS NS NS NS NS NS NS NS NS NS NS P < 0.05 NS
NS: Not significant (p > 0.1).
sions of the positive inotropic effects of glycosides. Our observations (Table I) indicate that the cardiotropic effects of BMO are similar to those of digoxin. For each, following intravenous administration, the onset for QS2I abbreviation was prompt and reached a maximum at 4 hr. After oral administration, the QS2I shortening was delayed, appearing at 40 min and reaching a maximum at 4 hr. At 24 hr the magnitude of the response to both agents was the same, whether the drugs were administered intravenously or orally. The time-course and the magnitude of serum glycoside levels following intravenous administration of BMO and digoxin were essentially the same. In contrast, following their ingestion, the serum glycoside levels of BMO were higher than those of digoxin throughout the initial 6-hr period, supporting earlier evidence of enhanced gastrointestinal absorption of BMO. 2.4,5, 7-9, 11 Following intravenous and oral administration, comparable serum glycoside levels for BMO were reached at 2 hr. In contrast, comparable serum glycoside levels were reached at 4 hr after intravenous and oral administration of digoxin (Fig. 5). It was found that for both drugs, 4 and 6 hr
after intravenous administration, there were greater (p < 0.001) positive inotropic effects than after oral administration (Fig. 5). These differences in inotropic response occurred at a time when the serum glycoside levels following intravenous and oral routes did not differ significantly (p > 0.5). These data suggest that following intravenous administration the initial higher serum levels probably result in higher glycoside concentration at the active sites in the myocardium (hence, the greater positive inotropic response) than are achieved when the glycosides enter the blood more gradually after ingestion. In contrast, the relatively small differences in the serum glycoside levels following oral administration of BMO and digoxin during the initial 6-hr period were not associated with detectable differences in positive inotropism and hence are probably insufficient to induce a greater concentration of BMO at the active myocardial sites. Our data indicate, therefore, that the higher serum glycoside levels achieved by greater gastrointestinal absorption of the BMO do not result in greater positive inotropic response (p > 0.5). These studies emphasize the need for independent measure of the cardiac inotropic responses in addition to the determination
Betamethyl digoxin and digoxin
Volume 22 Number 3
of the serum glycoside levels in the design of experiments aimed at the elucidation of newly developed glycosides.
9.
References 1. Forester, W., Lewis, R. P., Weissler, A. M., and Wilke, T. A.: The onset and magnitude of the contractile response to commonly used digitalis glycosides in normal subjects, Circulation 49:517-521, 1974. 2. Haberland, G.: Darstellung und Eigenschaften von Glykosidestern. Arzneim. Forsch. 15:481483, 1965. 3. Hartel, G., Manninen, V., Melin, J., et al.: Serum digoxin concentrations with a new digoxin derivative, betamethyl digoxin. Ann. Clin. Res. 5:87-90, 1973. 4. Kaiser, F.: Teilsynthetische HerzglykosideDerivate mit verbessester enteraler Wirksamkeit. 28. Mitteilung uber Herzglykoside, Planta Med. 4 (Suppl.):52-60, 1971. 5. Larbig, D., and Haasis, R.: Radiochemische Bestimmungen der Konzentration von Digoxin und Digoxin-Derivaten: Digitalis-therapie Beitrage zur Pharmakologie und Klinik, Berlin, 1975, Springer-Verlag, pp. 62-75. 6. Lewis, R. P., Leighton, R. F., Forester, W. F., and Weissier, A. M.: Noninvasive cardiology, New York, 1974, Grune & Stratton, Inc., pp. 301-368. 7. Megges, S. R., and Repke, K.: Uber Faktoren, welche die orale Wirksamkeit von Herzglykosiden bestimmen, Naunyn Schmiedebergs Arch. Pharmacol. 241:534, 1961. (Abst.) 8. Rennekamp, H., Rennekamp, C. H., Abshagen, U., Bergmann, K. V., and Rietbrock, N.: Pharmacokinetic behaviour of 4'" -methyl-
10.
11.
12.
13. 14.
15.
16.
285
digoxin in man, Naunyn Schmiedebergs Arch. Pharmacol. 273: 172-174, 1972. Rietbrock, N., Abshagen, U., von Bergmann, K., et al.: Pharmacokinetics of digoxin and its 4'" -acetyl- and methyl derivatives in the rat, Naunyn Schmiedebergs Arch. Pharmacol. 274: 171-181,1972. Smith, T. W., Butler, V. P., Jr., and Haber, E.: Determination of therapeutics and toxic serum digoxin concentrations by radioimmunoassay, N. Engl. 1. Med. 281:1212-1227, 1969. Weiss, W., Oieay, A., Teufel, W., and Glocke, M.: Glykosidkonzentrationen im serum bei Erhaltungstherapie mit Lanicor, Card-Lamuran, MF 708D and Lanitop, Med. Klin. 70: 13671374, 1975. Weissler, A. M., Gamel, W. G., Grode, H. E., et al.: The effects of digitalis on ventricular ejection in normal human subjects, Circulation 29:721-729, 1964. Weissler, A. M., Harris, W. S., Schoenfeld, C. D.: Systolic time intervals in heart failure in man, Circulation 37: 149-159, 1968. Weissler, A. M., Kamen, A. R., Bornstein, R. S., et al.: The effect of deslanoside on the duration of the phases of ventricular systole in man, Am. J. Cardiol. 15:153-161, 1965. Weissler, A. M., Lewis, R. P., Leighton, R. F., et al.: Validation of systolic time interval responses as a measure of the contractile effect of digitalis, in Basic and clinical pharmacology of digitalis, Proceedings of a symposium, Springfield, Ill., 1972, Charles C Thomas, Publisher, pp. 266-269. Weissler, A. M., Snyder, J. R., Schoenfeld, C. D., et al.: Assay of digitalis glycosides in man, Am. J. Cardiol. 17:768-780, 1966.
Gopal Das, M.D., Frederick N. Talmers, M.D., and Arnold M. Weissler, M.D. Allen Park and Detroit, Mich. Cardiology Section, Department of Medicine, Veterans Administration Hospital, and Wayne State University, School of Medicine
In previous studies 5 , 8, 9 enhanced and more complete gastrointestinal absorption of tritiumlabeled betamethyl digoxin (BMD) (a methyl derivative of digoxin) have been reported. Based on these studies, it was anticipated that the BMD given orally would result in a more rapid onset of action and greater cardiac effects than digoxin, an effect long desired in drugs Supported by a research grant from G. D. Searle & Co. Received for publication Feb. 7, 1977. Accepted for publication May 5, 1977. Reprint requests to: Gopal Das, F.A.C.C., Director, Cardiac Laboratories, Veterans Administration Hospital, Allen Park, Mich. 48101.
280
used in the treatment of congestive heart failure. Failure to find a systematic comparison of cardiac properties of the two drugs in the literature led us to evaluate and compare the positive inotropic properties of BMD and digoxin in man. The systolic time interval response to digitalis glycoside offers a convenient noninvasive method of studying serial changes in the left ventricular inotropic response to these drugs. This method lends itself to comparison of the cardiac responses to the various glycosides over prolonged study periods and hence provides the opportunity to test the hypothe-
Betamethyl digoxin and digoxin
Volume 22 Number 3
sis that increased absorption results in greater cardiac response to BMD than to digoxin. The positive inotropic effects and the serum glycoside levels following intravenous and oral administration of BMD were measured and compared with those of digoxin in normal adult volunteers. The cardiac inotropy was assessed noninvasively in the abbreviation of the electromechanical systolic time index (QS2I) obtained in serial measurements of systolic time intervals.
o
-30
I
3m
I
5m
--e--
BMD (I.V.)
-0-
Digoxin (IV)
I
10
I
20
I
I
40 Ih
I
2
I
I
4 6
281
I
24h
Time
Materials and methods
Studies were performed on 5 healthy volunteers aged 22 to 34. In none were cardiac abnormalities detected by a complete physical examination, chest roentgenographic and electrocardiographic examinations. Each subject received 0.8 mg BMD intravenously, 0.8 mg digoxin intravenously, 0.8 mg BMD orally, and 0.75 mg digoxin orally at 4- to 6-wk intervals. The drugs were selected at random and were administered in a single dose. The cardiac responses for each regimen were measured by the noninvasive technique of systolic time intervalS. 13 The subjects were studied in the postabsorptive state. Starting at 8:00 A.M., an indwelling catheter was placed in a vein in the left arm and was used to collect blood samples for digitalis assay. Blood samples were collected immediately following each systolic time interval recording. The serum glycoside activity was measured by the radioimmunoassay technique with the use of Schwartz-Man kit and were expressed as nanograms per milliliter. 10 The two drugs are indistinguishable in the assay by this kit and in our laboratory the technique is insensitive to serum glycoside activity below 0.4 ng/ml. Since digoxin is a significant metabolite of BMD in man, such a conversion will not alter the serum glycoside levels because the test is equally sensitive to both. The systolic time intervals were measured from simultaneous fast speed (100 mm/sec) photographic recordings of an electrocardiographic lead, a phonocardiogram, and a carotid arterial pulse tracing with time markers indicating 40-msec intervals. The phonocardiogram was obtained by use of a contact microphone
Fig. 1. Comparison of positive inotropic responses (QS21 abbreviation, mean ± SEM) to intravenous administration of BMO and digoxin. For each drug onset of action was prompt (within 3 min) and a maximal response occurred at 4 hr following the intravenous administration.
(PSI-Electronics for Medicine) and the carotid arterial pulsations were recorded through a 2.3-cm diameter funnel-shaped pick-up, air coupled to a P23db Statham transducer. Following 30 min of supine rest after the catheter placement, three baseline systolic time interval recordings and blood samples were obtained 10 min apart, and an average of these three observations was used as a control. The BMD or digoxin was administered either in a vein in the right arm or was swallowed with a little water. The systolic time interval recordings and the blood samples were repeated at 3, 5, 10, 20, and 40 min and 1, 2, 4, 6, and 24 hr following the drug administration. The cardiac cycle length (R-R interval), electromechanical systolic time (QS2, measured from the beginning of the QRS complex to the first high-frequency vibration of the second heart sound), and the left ventricular ejection time (L VET, an interval from the beginning to the trough of the incisural notch on the carotid arterial pulse tracing) were measured in 10 consecutive cycles and averaged as described previously.13 The pre-ejection period (PEP) was calculated by subtracting L VET from the QS2' Heart rate was derived by dividing R-R into 60 and was expressed to the nearest integer. The electromechanical systolic time, the left ventricular ejection time, and the pre-ejection period were corrected for the heart rate by means of perviously derived regression equations relating the heart rate and the systolic
282
Das, Talmers, and Weissler
Clinical Pharmacology and Therapeutics
10
--e-- BMD (I.v.) - 0 - Digoxin (IV.)
o .~ 20 o
]
0>
o
Ji'
~
o
Q)
-10
10
-20 _.-.. -.- BMD (P.O.) Digoxin (P.OJ
-0-
Time
Fig. 2. Comparison of serum glycoside levels (mean ± SEM) to intravenous administration of BMO and digoxin.
intervals in normal men and were expressed as electromechanical systolic index (QS21), the left ventricular ejection time index (L VETI) , and pre-ejection period index (PEPI), respectively.6 The abbreviation in these intervals was ploUed against time for each drug. The time constant for the glycoside action following intravenous administration was calculated as described by Forester and co-workers.! Results
Since the molar weights of the two glycosides were so similar (794.94 for BMD and 780.92 for digoxin), correction for this variable was not introduced in the data analysis. The magnitude of maximum QS2I abbreviation in response to both drugs compared with that for L VETI and PEPI was greater and had less variance (QS2I, 23 ± l.9 [SEMj; L VETI, 19 ± 1.9; and PEPI, 10 ± 1.5). Thus the significance of QS2I response was greater than that for LVETI and PEPI (t = 12.3, 10.3, and 7.1, respectively). The comparison of inotropic responses to intravenous administration of BMD and digoxin is shown in Fig. 1. The effect of BMD was apparent within 3 min and gradually increased to a maximum abbreviation of 25 msec at 4 hr. The effect of digoxin was also apparent within 3 min and reached a maximum of 21 msec at 4 hr. The time constants for BMD and digoxin action were 27 and 25 min, respectively. The differences in time course and
-30
~m
5m
It>
26 4b Ih
I
2
I
24h
Time
Fig. 3. Comparison of positive inotropic responses (QS21 abbreviation, mean ± SEM) to oral administration of BMO and digoxin. The onset of action for both drugs was delayed to 40 min and a maximal response occurred at 4 hr following ingestion.
the relative magnitude of the cardiac effects of the two drugs as measured by the time of onset, magnitude of maximum response, time of maximum response, time constant of action, and the area under the response curve were not significant (p > 0.2). The relative magnitude and the time course of the serum glycoside levels following intravenous administration of the two drugs, shown in Fig. 2, were also not different (p > 0.2). The areas under the glycoside curves were 61.7 ± 4.0 (SEM) and 58.5 ± 4.3 (p > 0.4) cm 2 for BMD and digoxin, respectively. Following the oral administration of BMD, the onset of response in QS2I abbreviation appeared at 40 min and reached a maximum of 12 msec at 4 hr (Fig. 3). The time of onset, the magnitude of response, time course of response, and the area under the QS2I curve were not different from those after oral administration of digoxin (p > 0.5). The serum glycoside activity after the oral administration of the two glycosides, however, was different. In 4 of the 5 subjects the glycoside appeared in the blood within 20 min after ingestion of BMD and 40 min (p > 0.2) after digoxin. Thereafter serum levels (Fig. 4) were consistently higher for BMD than those for digoxin up to 6 hr after administration (p
0.5), as illustrated in the lower panel.
greater significance. 14 These findings were confirmed in our study. The abbreviation in the systolic intervals following glycoside administration is unaccompanied by change in the slope of the regression line relating these intervals to heart rate. 14 It has also been documented that the abbreviation in the systolic intervals by glycosides is dose-dependent and closely correlated (r = 0.90) with other independent measures of the left ventricular inotropic responses. 15 These data provide evidence that the systolic interval responses are accurate expres-
284
Das, Talmers, and Weissler
Clinical Pharmacology and Therapeutics
Table I. Comparative pharmacodynamics of betamethyl digoxin and digoxin
Parameter Intravenous administration Onset of QS2I abbreviation Time to maximum response (hr) Time constant of action (min) Magnitude of maximum response (msec, ±SEM) Area under the QS2I response curves (cm2 ± SEM) Peak serum glycoside level (ng/ml, ±SEM) Area under serum glycoside curves (cm2 ±SEM) Oral administration Onset of QS2I abbreviation (min) Time to maximum response (hr) Magnitude of maximum response (msec, ±SEM) Area under the QS2I response curves (cm2' ±SEM) Onset of glycoside appearance in blood (min) Peak serum glycoside level (ng/ml, ±SEM) Area under the serum glycoside curves (cm2, ± SEM)
Betamethyl digoxin (molar weight, 794.94)
Digoxin (molar weight, 780.92)
0.8 mg Immediate (within 3 min) 4 27 25 ± 2.2 70.7 ± 12.7 26.2 ± 3.3 61.7 ± 4.0 0.8 mg 40 4 12 ± 3.1 34.3 ± 8.2 20 3.3 ± 0.68 11.4 ± 2.9
0.8 mg Immediate (within 3 min) 4 25 21 ± 4.0 60.2 ± 9.7 30.1 ± 5.3 58.5 ± 4.3 0.75 mg 40 4 13 ± 3.1 33.4 ± 7.3 40 1.6 ± 0.45 5.0 ± 0.9
Significance NS NS NS NS NS NS NS NS NS NS NS NS P < 0.05 NS
NS: Not significant (p > 0.1).
sions of the positive inotropic effects of glycosides. Our observations (Table I) indicate that the cardiotropic effects of BMO are similar to those of digoxin. For each, following intravenous administration, the onset for QS2I abbreviation was prompt and reached a maximum at 4 hr. After oral administration, the QS2I shortening was delayed, appearing at 40 min and reaching a maximum at 4 hr. At 24 hr the magnitude of the response to both agents was the same, whether the drugs were administered intravenously or orally. The time-course and the magnitude of serum glycoside levels following intravenous administration of BMO and digoxin were essentially the same. In contrast, following their ingestion, the serum glycoside levels of BMO were higher than those of digoxin throughout the initial 6-hr period, supporting earlier evidence of enhanced gastrointestinal absorption of BMO. 2.4,5, 7-9, 11 Following intravenous and oral administration, comparable serum glycoside levels for BMO were reached at 2 hr. In contrast, comparable serum glycoside levels were reached at 4 hr after intravenous and oral administration of digoxin (Fig. 5). It was found that for both drugs, 4 and 6 hr
after intravenous administration, there were greater (p < 0.001) positive inotropic effects than after oral administration (Fig. 5). These differences in inotropic response occurred at a time when the serum glycoside levels following intravenous and oral routes did not differ significantly (p > 0.5). These data suggest that following intravenous administration the initial higher serum levels probably result in higher glycoside concentration at the active sites in the myocardium (hence, the greater positive inotropic response) than are achieved when the glycosides enter the blood more gradually after ingestion. In contrast, the relatively small differences in the serum glycoside levels following oral administration of BMO and digoxin during the initial 6-hr period were not associated with detectable differences in positive inotropism and hence are probably insufficient to induce a greater concentration of BMO at the active myocardial sites. Our data indicate, therefore, that the higher serum glycoside levels achieved by greater gastrointestinal absorption of the BMO do not result in greater positive inotropic response (p > 0.5). These studies emphasize the need for independent measure of the cardiac inotropic responses in addition to the determination
Betamethyl digoxin and digoxin
Volume 22 Number 3
of the serum glycoside levels in the design of experiments aimed at the elucidation of newly developed glycosides.
9.
References 1. Forester, W., Lewis, R. P., Weissler, A. M., and Wilke, T. A.: The onset and magnitude of the contractile response to commonly used digitalis glycosides in normal subjects, Circulation 49:517-521, 1974. 2. Haberland, G.: Darstellung und Eigenschaften von Glykosidestern. Arzneim. Forsch. 15:481483, 1965. 3. Hartel, G., Manninen, V., Melin, J., et al.: Serum digoxin concentrations with a new digoxin derivative, betamethyl digoxin. Ann. Clin. Res. 5:87-90, 1973. 4. Kaiser, F.: Teilsynthetische HerzglykosideDerivate mit verbessester enteraler Wirksamkeit. 28. Mitteilung uber Herzglykoside, Planta Med. 4 (Suppl.):52-60, 1971. 5. Larbig, D., and Haasis, R.: Radiochemische Bestimmungen der Konzentration von Digoxin und Digoxin-Derivaten: Digitalis-therapie Beitrage zur Pharmakologie und Klinik, Berlin, 1975, Springer-Verlag, pp. 62-75. 6. Lewis, R. P., Leighton, R. F., Forester, W. F., and Weissier, A. M.: Noninvasive cardiology, New York, 1974, Grune & Stratton, Inc., pp. 301-368. 7. Megges, S. R., and Repke, K.: Uber Faktoren, welche die orale Wirksamkeit von Herzglykosiden bestimmen, Naunyn Schmiedebergs Arch. Pharmacol. 241:534, 1961. (Abst.) 8. Rennekamp, H., Rennekamp, C. H., Abshagen, U., Bergmann, K. V., and Rietbrock, N.: Pharmacokinetic behaviour of 4'" -methyl-
10.
11.
12.
13. 14.
15.
16.
285
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