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Pharmacokinetics of molsidomine in humans
Pharmacokinetics
of molsidomine
in humans
The pharmacokinetics of molsidomine were investigated in the plasma and urine of healthy male volunteers and patients with coronary heart disease after intravenous and/or oral administration of different galenic dosage forms of molsidomine. Following the rapid attainment of mean peak concentration (15 rt 7 mg/ml) 0.5 to 1.0 hour after single oral dosing of 2 mg of molsidomine, the plasma levels of the unchanged drug decline monoexponentially with a mean half-life of 1.6 + 0.8 hours. Molsidomine is absorbed almost completely. Its absolute bioavailability (44 + 15%) and a “C-labeled triale give evidence of quick biotransformation of molsidomine to active metabolites. Less than 2% of the unchanged drug appear in the urine, but renal excretion is the main route of elimination of the metabolites in humans (90% to 95%). The kinetic parameters after administration of multiple dosages of 4 mg of molsidomine over 29 days do not account for accumulation of or enzyme induction by molsidomine. The finding of obvious good correlations between plasma levels of the predrug molsidomine and corresponding pharmacodynamic data can be made plausible by the time course of concentration values of the active metabolite SIN-1 in plasma. (AM HEART J lOg:641, 1985.)
J. Ostrowski,
Ph.D., and K. Resag, Ph.D. Frankfurt/Main,
The antianginal drug molsidomine (N-carboxy-3morpholino-sydnonimine-ethylester) is effective in patients with coronary heart disease for up to 3 to 5 hours after a single oral dose of 2 mg. Plasma levels of the parent drug can also be measured quantitatively during this period. The purpose of this report is to summarize and discuss two aspects of the pharmacokinetics of molsidomine-the availability and safety of the drug and the correlation of the pharmacokinetic data to the corresponding pharmacodynamic results. METHODS
Five distinct study protocols were followed-two in healthy volunteers’~” and three in patients with coronary heart disease.3-5 Common to all protocols was measurement of molsidomine by means of a selective highperformance liquid column chromatography method.6The pharmacologically active metabolite SIN-l was determined by transfer catalysis prior to high-performance liquid column chromatography analysis (C. D. Bevan, unpublished data). RESULTS
AND
Availability
DISCUSSION and
safety.
nous bolus injection
From the Department Cassella AG.
Following a single intraveof 2 mg of molsidomine in
of Pharmaceutical
Reprint requests: J. Ostrowski, Abteilung Biochemie, Hanauer West Germany.
Ph.D., Landstrasse
Research
and
Development,
Cassella AG, Pharmaforschung, 526,600O Frankfurt/Main
61,
West Germany
healthy male volunteers1 the mean molsidomine plasma concentration-time profile is adequately described by a biexponential equation starting at about 70 ng of molsidomine/ml and decreasing with a terminal half-life of 1.6 hours. The maximum mean plasma level after single oral crossover administration of 2 mg of molsidomine (Corvaton) was achieved at approximately 0.5 to 1.0 hour. The elimination half-lives for both the orally and intravenously administered drug are equivalent. The drug is absorbed completely as estimated from a 14C-labeled balance study. This process occurs with a mean time of about 15 minutes (absorption time = mean system time - mean time of total body model) (Table I). The total plasma clearance is in the range of 1 L/min, and since this approximates liver blood flow it would indicate that the liver is a major metabolizing organ. This may account for the 44% absolute bioavailability of the drug and would suggest the possibility of first-pass metabolism.’ However, this is a desirable and necessary step because molsidomine is a predrug. The molsidomine concentration in plasma and the listed pharmacokinetic parameters all exhibit considerable intersubject variability, which is to be expected for “high-clearance” drugs. Ninety to ninety-five percent of total radioactivity is renally excreted after oral administration of 14C-labeled molsidomine.2 Less than 2% of the drug appears unchanged in urine. Three to four percent of the radioactivity is found in the feces (Table I). 641
March,
642
Ostrowski
and Resag
American
i
4
1
1
I
1
2
3
4
adays
Fig. 1. Recorded (solid circles) and simulated plasma levels after oral administration Corvaton forte (four doses of 4 mg/day, at 7:00, ll:OO, 15:00, and 19:OO).
Table I. Kinetic parameters istration of 2 mg in humans
of molsidomine
after admin-
Parameter Absorption and distribution Absorption time (hr) Peak plasma concentration (w/ml) Time to peak plasma concentration (hr) Absolute bioavailability (S) Total plasma clearance (L/hr) Volume of distribution at steady state (L) Mean system time (hr) Mean time of total body model (hr) Protein binding (Z ) Elimination Plasma terminal half-life (hr) Renal excretion (“0 ) (Tb ‘“C) Fecal excretion (? “C) Multiple dose regimen Accumulation index (At 2 2-3
Value 0.23 15 2 I 0.5-1.0 44 _t 15 46 k 20 98 * 48 2.06
1.83 0 1.6 + 0.8 <2 90-95 3-4 -1
hr)
Multiple dose administration do not account for accumulation of or enzyme induction by molsidomine when the dosage interval is at least 2 to 3 hours. Fig. 1 shows an example of long-term treatment with four doses of 4 mg Corvaton forte daily of patients with myocardial infarction.3 The recorded mean molsidomine plasma levels on day 29 were very
of multiple
Heart
1985 Journal
doses of
similar to those after the first administration of the drug on day 1. Physiologic correlates. There seems to be some kind of relationship between the plasma level and the antianginal efficacy of molsidomine. This aspect is important for two reasons. First, molsidomine is a predrug. Assuming that the pharmacokinetics and pharmacodynamics really do correlate one must conclude that either hydrolysis and decarboxylation of molsidomine to the pharmacologically active metabolite SIN-l or parent drug return from the periphery to the liver is the rate-limiting step in the metabolic pathway of molsidomine. The degradation of SIN-l must be faster than its formation. Second, molsidomine can be determined in plasma much easier than SIN-l. The pH- and temperaturedependent lability and the very low concentrations of SIN-l in plasma bring great analytic problems. There are representative examples supporting the working hypothesis of correlation. Strasser et al.4 have shown that there is an obviously good linear correlation between plasma levels of the predrug molsidomine and the ST segment depression in coronary heart disease patients after single oral or sublingual administration of 2 mg of Corvaton. A threshold of efficacy is discussed because of the intercept of the line with the x axis at 3 to 5 ng of molsidomine/ml. Ostrowski et a1.5 have compared the time course of the change of the diastolic diameter of the left ventricle of the heart in coronary heart disease patients with the time course of the
Volume Number
109 3, Part 2
Pharmacokinetics
105
dpm/ml
A
1
6
103
rig/ml
1
12 hours
643
B
6 hours
Fig. 2. Individual plasmalevels of molsidomine(open circles) and SIN-l (solid circles) after single oral dosesof 10 mg of YXabeled molsidomine/kg in dog (A) and 16 mg of Corvaton in humans (B).
corresponding molsidomine plasma level. The semilogarithmic plot shows a parallel decline of both curves with a half-life of approximately 1.8 hours. When the dynamic data are plotted vs the corresponding plasma levels of molsidomine, a counterclockwise hysteresis-like loop is formed. Both studies show an obvious correlation between the dynamic response and the plasma level of the predrug, at least in respect to the descending part of the curves. The data would be still more convincing if one gives evidence that the kinetics of the predrug reflect the kinetics of SIN-l. That is the case, indeed. From dog experiments (C. D. Bevan, unpublished data) and studies in healthy volunteers7 it can be seen that the kinetic profiles of molsidomine and its pharmacologically active metabolite SIN-l are very similar (Fig. 2). The molsidomine derived kinetics of SIN-l are a so-called flip-flop case where the half-life of the descending part of the plasma level characterizes the formation of SIN-l from molsidomine. This half-life does not describe the process of elimination. CONCLUSIONS
There are convincing data that the molsidominemediated dynamic response can be correlated to the plasma level of the predrug itself, at least to the descending part of the curve. Physicians are thereby
provided with a tool to estimate the duration and half-life of the clinical effects from molsidomine plasma levels. From the analytic point of view molsidomine plasma level is a kind of welcome amplifier of SIN-l kinetics useful to overcome the difficult analytic handling of the SIN-l determination. REFERENCES
1. Bergstrand R, Vedin A, Wilhelmsson C, Peterson LE, Chamberlain J, Dell D, Stevens LA, Ostrowski J: Intravenous and oral dosing of molsidomine: A pharmacodynamic and pharmacokinetic study. Eur J Clin Pharmacol 27:203, 1984. 2. Dell D, Fromson JM, Illing HPA, Johnson KI, McEwen J: Pharmacokinetics and pharmacodynamics of molsidomine in man. Br J Clin Pharmacol5:395P, 1978. 3. Oltmanns D. Friedmann W. Ostrowski J: Zur Pharmakokinetik von Molsidomin bei hochdosierter Langzeitbehandlung des frischen Herzinfarktes. Herzmedizin 5:141, 1982. 4. Strasser R, Klepzig H, Ostrowski J, Resag K: Molsidomin bei koronarer Herzkrankheit: Klinisch-pharmakokinetische Korrelationsstudie iiber die Wirkung der oralen und sublingualen Therapie. MMW 125:156, 1983. 5. Ostrowski J, Schweizer P, Erbel R, Claus G, Resag K: Correlation of pharmacokinetic data to clinical effect of molsidomine. In Aiache JM, Hirtz J, editors: Proceedings of the First European Congress of Biopharmaceutics and Pharmacokinetics, ~013: Technique et documentation, ClermondFerrand, Apr l-3, 1981, p 418. 6. Dell D, Chamberlain J: Determination of molsidomine in plasma by high performance liquid column chromatography. J Chromatogr 146:465, 1978. 7. Wildgrube HJ, Ostrowski J, Stockhausen H, Gartner W, Robinson JD: Leberfunktion und Pharmakokinetik von Molsidomin und SIN 1 bei gesunden Probanden (submitted to Arzneimittelforsch [Drug Res]).
of molsidomine
in humans
The pharmacokinetics of molsidomine were investigated in the plasma and urine of healthy male volunteers and patients with coronary heart disease after intravenous and/or oral administration of different galenic dosage forms of molsidomine. Following the rapid attainment of mean peak concentration (15 rt 7 mg/ml) 0.5 to 1.0 hour after single oral dosing of 2 mg of molsidomine, the plasma levels of the unchanged drug decline monoexponentially with a mean half-life of 1.6 + 0.8 hours. Molsidomine is absorbed almost completely. Its absolute bioavailability (44 + 15%) and a “C-labeled triale give evidence of quick biotransformation of molsidomine to active metabolites. Less than 2% of the unchanged drug appear in the urine, but renal excretion is the main route of elimination of the metabolites in humans (90% to 95%). The kinetic parameters after administration of multiple dosages of 4 mg of molsidomine over 29 days do not account for accumulation of or enzyme induction by molsidomine. The finding of obvious good correlations between plasma levels of the predrug molsidomine and corresponding pharmacodynamic data can be made plausible by the time course of concentration values of the active metabolite SIN-1 in plasma. (AM HEART J lOg:641, 1985.)
J. Ostrowski,
Ph.D., and K. Resag, Ph.D. Frankfurt/Main,
The antianginal drug molsidomine (N-carboxy-3morpholino-sydnonimine-ethylester) is effective in patients with coronary heart disease for up to 3 to 5 hours after a single oral dose of 2 mg. Plasma levels of the parent drug can also be measured quantitatively during this period. The purpose of this report is to summarize and discuss two aspects of the pharmacokinetics of molsidomine-the availability and safety of the drug and the correlation of the pharmacokinetic data to the corresponding pharmacodynamic results. METHODS
Five distinct study protocols were followed-two in healthy volunteers’~” and three in patients with coronary heart disease.3-5 Common to all protocols was measurement of molsidomine by means of a selective highperformance liquid column chromatography method.6The pharmacologically active metabolite SIN-l was determined by transfer catalysis prior to high-performance liquid column chromatography analysis (C. D. Bevan, unpublished data). RESULTS
AND
Availability
DISCUSSION and
safety.
nous bolus injection
From the Department Cassella AG.
Following a single intraveof 2 mg of molsidomine in
of Pharmaceutical
Reprint requests: J. Ostrowski, Abteilung Biochemie, Hanauer West Germany.
Ph.D., Landstrasse
Research
and
Development,
Cassella AG, Pharmaforschung, 526,600O Frankfurt/Main
61,
West Germany
healthy male volunteers1 the mean molsidomine plasma concentration-time profile is adequately described by a biexponential equation starting at about 70 ng of molsidomine/ml and decreasing with a terminal half-life of 1.6 hours. The maximum mean plasma level after single oral crossover administration of 2 mg of molsidomine (Corvaton) was achieved at approximately 0.5 to 1.0 hour. The elimination half-lives for both the orally and intravenously administered drug are equivalent. The drug is absorbed completely as estimated from a 14C-labeled balance study. This process occurs with a mean time of about 15 minutes (absorption time = mean system time - mean time of total body model) (Table I). The total plasma clearance is in the range of 1 L/min, and since this approximates liver blood flow it would indicate that the liver is a major metabolizing organ. This may account for the 44% absolute bioavailability of the drug and would suggest the possibility of first-pass metabolism.’ However, this is a desirable and necessary step because molsidomine is a predrug. The molsidomine concentration in plasma and the listed pharmacokinetic parameters all exhibit considerable intersubject variability, which is to be expected for “high-clearance” drugs. Ninety to ninety-five percent of total radioactivity is renally excreted after oral administration of 14C-labeled molsidomine.2 Less than 2% of the drug appears unchanged in urine. Three to four percent of the radioactivity is found in the feces (Table I). 641
March,
642
Ostrowski
and Resag
American
i
4
1
1
I
1
2
3
4
adays
Fig. 1. Recorded (solid circles) and simulated plasma levels after oral administration Corvaton forte (four doses of 4 mg/day, at 7:00, ll:OO, 15:00, and 19:OO).
Table I. Kinetic parameters istration of 2 mg in humans
of molsidomine
after admin-
Parameter Absorption and distribution Absorption time (hr) Peak plasma concentration (w/ml) Time to peak plasma concentration (hr) Absolute bioavailability (S) Total plasma clearance (L/hr) Volume of distribution at steady state (L) Mean system time (hr) Mean time of total body model (hr) Protein binding (Z ) Elimination Plasma terminal half-life (hr) Renal excretion (“0 ) (Tb ‘“C) Fecal excretion (? “C) Multiple dose regimen Accumulation index (At 2 2-3
Value 0.23 15 2 I 0.5-1.0 44 _t 15 46 k 20 98 * 48 2.06
1.83 0 1.6 + 0.8 <2 90-95 3-4 -1
hr)
Multiple dose administration do not account for accumulation of or enzyme induction by molsidomine when the dosage interval is at least 2 to 3 hours. Fig. 1 shows an example of long-term treatment with four doses of 4 mg Corvaton forte daily of patients with myocardial infarction.3 The recorded mean molsidomine plasma levels on day 29 were very
of multiple
Heart
1985 Journal
doses of
similar to those after the first administration of the drug on day 1. Physiologic correlates. There seems to be some kind of relationship between the plasma level and the antianginal efficacy of molsidomine. This aspect is important for two reasons. First, molsidomine is a predrug. Assuming that the pharmacokinetics and pharmacodynamics really do correlate one must conclude that either hydrolysis and decarboxylation of molsidomine to the pharmacologically active metabolite SIN-l or parent drug return from the periphery to the liver is the rate-limiting step in the metabolic pathway of molsidomine. The degradation of SIN-l must be faster than its formation. Second, molsidomine can be determined in plasma much easier than SIN-l. The pH- and temperaturedependent lability and the very low concentrations of SIN-l in plasma bring great analytic problems. There are representative examples supporting the working hypothesis of correlation. Strasser et al.4 have shown that there is an obviously good linear correlation between plasma levels of the predrug molsidomine and the ST segment depression in coronary heart disease patients after single oral or sublingual administration of 2 mg of Corvaton. A threshold of efficacy is discussed because of the intercept of the line with the x axis at 3 to 5 ng of molsidomine/ml. Ostrowski et a1.5 have compared the time course of the change of the diastolic diameter of the left ventricle of the heart in coronary heart disease patients with the time course of the
Volume Number
109 3, Part 2
Pharmacokinetics
105
dpm/ml
A
1
6
103
rig/ml
1
12 hours
643
B
6 hours
Fig. 2. Individual plasmalevels of molsidomine(open circles) and SIN-l (solid circles) after single oral dosesof 10 mg of YXabeled molsidomine/kg in dog (A) and 16 mg of Corvaton in humans (B).
corresponding molsidomine plasma level. The semilogarithmic plot shows a parallel decline of both curves with a half-life of approximately 1.8 hours. When the dynamic data are plotted vs the corresponding plasma levels of molsidomine, a counterclockwise hysteresis-like loop is formed. Both studies show an obvious correlation between the dynamic response and the plasma level of the predrug, at least in respect to the descending part of the curves. The data would be still more convincing if one gives evidence that the kinetics of the predrug reflect the kinetics of SIN-l. That is the case, indeed. From dog experiments (C. D. Bevan, unpublished data) and studies in healthy volunteers7 it can be seen that the kinetic profiles of molsidomine and its pharmacologically active metabolite SIN-l are very similar (Fig. 2). The molsidomine derived kinetics of SIN-l are a so-called flip-flop case where the half-life of the descending part of the plasma level characterizes the formation of SIN-l from molsidomine. This half-life does not describe the process of elimination. CONCLUSIONS
There are convincing data that the molsidominemediated dynamic response can be correlated to the plasma level of the predrug itself, at least to the descending part of the curve. Physicians are thereby
provided with a tool to estimate the duration and half-life of the clinical effects from molsidomine plasma levels. From the analytic point of view molsidomine plasma level is a kind of welcome amplifier of SIN-l kinetics useful to overcome the difficult analytic handling of the SIN-l determination. REFERENCES
1. Bergstrand R, Vedin A, Wilhelmsson C, Peterson LE, Chamberlain J, Dell D, Stevens LA, Ostrowski J: Intravenous and oral dosing of molsidomine: A pharmacodynamic and pharmacokinetic study. Eur J Clin Pharmacol 27:203, 1984. 2. Dell D, Fromson JM, Illing HPA, Johnson KI, McEwen J: Pharmacokinetics and pharmacodynamics of molsidomine in man. Br J Clin Pharmacol5:395P, 1978. 3. Oltmanns D. Friedmann W. Ostrowski J: Zur Pharmakokinetik von Molsidomin bei hochdosierter Langzeitbehandlung des frischen Herzinfarktes. Herzmedizin 5:141, 1982. 4. Strasser R, Klepzig H, Ostrowski J, Resag K: Molsidomin bei koronarer Herzkrankheit: Klinisch-pharmakokinetische Korrelationsstudie iiber die Wirkung der oralen und sublingualen Therapie. MMW 125:156, 1983. 5. Ostrowski J, Schweizer P, Erbel R, Claus G, Resag K: Correlation of pharmacokinetic data to clinical effect of molsidomine. In Aiache JM, Hirtz J, editors: Proceedings of the First European Congress of Biopharmaceutics and Pharmacokinetics, ~013: Technique et documentation, ClermondFerrand, Apr l-3, 1981, p 418. 6. Dell D, Chamberlain J: Determination of molsidomine in plasma by high performance liquid column chromatography. J Chromatogr 146:465, 1978. 7. Wildgrube HJ, Ostrowski J, Stockhausen H, Gartner W, Robinson JD: Leberfunktion und Pharmakokinetik von Molsidomin und SIN 1 bei gesunden Probanden (submitted to Arzneimittelforsch [Drug Res]).