Xenobiotica the fate of foreign compounds in biological systems
ISSN: 0049-8254 (Print) 1366-5928 (Online) Journal homepage: http://www.tandfonline.com/loi/ixen20
Pharmacokinetic characteristics of bornaprolol in healthy volunteers G. Cheymol, A. Cheymol, C. Jozefczak, V. Lecoq, B. Lecoq & P. Jaillon To cite this article: G. Cheymol, A. Cheymol, C. Jozefczak, V. Lecoq, B. Lecoq & P. Jaillon (1990) Pharmacokinetic characteristics of bornaprolol in healthy volunteers, Xenobiotica, 20:8, 855-860 To link to this article: http://dx.doi.org/10.3109/00498259009046899
Published online: 27 Aug 2009.
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Date: 06 November 2015, At: 05:26
XENOBIOTICA,
1990, VOL. 20,
NO.
8, 855-860
Pharmacokinetic characteristics of bornaprolol in healthy volunteers G. CHEYMOLtS, A. CHEYMOL, C. JOZEFCZAKg, V. LECOQT, B. LECOQT and P. JAILLONT Downloaded by [University of California Santa Barbara] at 05:26 06 November 2015
t Service de Pharmacologie, H6pital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France § Phamuka Laboratories, Gennevilliers, France 7 Unit6 de Pharmacologie Clinique, H6pital Saint-Antoine, Paris, France
Received 15 July 1988; accepted 21 April 1990 1. Six young male volunteers received five single doses of bornaprolol, i.v. (20 mg) and orally (120, 240,480,960 mg) administered at 2-week intervals. Plasma concentrations of bornaprolol and its conjugated metabolite were determined by gas chromatography. 2. After i.v. administration, plasma bornaprolol levels were detectable over 8 h, and mean values were 60 l/h for total clearance (Cl), 207 1 for volume of distribution ( Vs),2 6 h for elimination half-life (tl12#). After oral administration, plasma bornaprolol levels were detectable over 24-48 h, and mean values of pharmacokinetics parameters were 601/hfor C1,1500 1for Vr,20 h for t1,*#.Maximum plasma concentrations and area under the plasma concentration-time curve increased in a non-dose-dependent manner. 3. The glucuronide conjugate appeared in the blood within 5-l0min and its plasma level greatly exceeded bornaprolol concentrations. The mean value of the ratio of the metabolite AUC/parent product AUC was 14 after i.v. administration and 13-21 following oral administration, depending on dose. The AUC for the metabolite did not increase proportionally with oral doses. 4. Bornaprolol is principally eliminated after metabolism. This process did not increase with increasing oral doses and bioavailability seemed to decrease inversely with oral dose.
Introduction Bornaprolol, a norbornyl derivative, is a new, non-cardioselective /?-blocker, possessing prolonged /?-adrenergic antagonistic activity on receptors in vitro and in vivo. In vitro, bornaprolol inhibits isoproterenol-inducedstimulation of adenylate cyclase in rat heart homogenate; this inhibition was apparently non-dissociable since it could not be reversed either by addition of an excess of isoproterenol, or by washing (Le Fur et al. 1978). In mice, bornaprolol induced durable blockade of /3receptors in the heart, brain and lungs (Le Fur et al. 1980). In conscious dogs, bornaprolol was equipotent to propranolol on isoproterenol-induced tachycardia, but its duration of action was 2-3 times longer (Mestre et 01.1978). This prolonged inhibition could not be correlated with tissue levels of labelled bornaprolol, and appeared to be related to very slow dissociable binding to /?-receptors(Le Fur et al. 1980, 1981). The results of a study after single oral administration to healthy volunteers confirmed data obtained in animals (Cheymol et af. 1987). Bornaprolol induced prolonged cardiovascular/?-blockade,the duration of which depended on dosage and type of protocol, namely from 24 h (120-240 mg bornaprolol) to 48 h (480-960 mg) for hypertension and exercise-induced tachycardia, and over 72 h for isoproterenolinduced tachycardia (80, 160, 240mg). $ T o whom correspondence should be addressed. M)49-8254)90 S3.W 0 1990 Taylor 8z Francis Ltd.
856
G. Cheymol et al.
Preliminary investigations in dogs and man have shown low plasma levels of unchanged drug and high concentrations of the glucuronide conjugate, associated with low urinary excretion of the parent drug, equivalent to less than 1% of oral and i.v. doses administered (A. Uzan 1986, personal communication). The objective of the present study was to determine the plasma pharmacokinetic characteristics of bornaprolol in health volunteers.
Downloaded by [University of California Santa Barbara] at 05:26 06 November 2015
Subjects and methods Subjects The study was carried out in healthy male volunteers (age 26-34 years, weight 60-80 kg, height 17Ck 190cm), who had previously undergone a physical examination and laboratory tests to exclude subjects presenting any contraindication to 8-blockers. All gave their informed consent to participate in the study, and were not taking medication. The protocol was approved by the ethics committee of the Saint-Antoine hospital. Drug Bornaprolol is (+)-1-(2-exo-bicyclo [2,2,l]hept-2-ylphenoxy)-3-[(l-methylethyl)amino]-2propanol hydrochloride (50 :50 mixture of the two racemic diastereoisomers).
Plasma kinetics Single intravenous (20mg) and oral doses (120, 240, 480, 960mg) of bornaprolol were given to six subjects. Doses were administered at 2-week intervals, in the morning after an overnight fast, followed 2 h later by a light breakfast. For oral administration, the product was taken as an aqueous suspension. Blood pressure and heart rate were monitored during the study. After oral administration, blood samples were nd collectedat 10,20,30,45min, 1 , 1 ~ 5 , 2 , 2 ~ 5 , 3 , 4 , 5 , 6 , 8 , 1 0 , 1 1 , 2 3 , 4 7 , 7 1 , 9 5 , 1 1 9 , 1 4 3 a 167h.Afteri.v. administration, additional samples were collected during the first 10 min. Plasma samples were stored at - 20°C until assay. Assays Plasma concentrations of bornaprolol and its glucuronide conjugated were determined by g.1.c. (Bernard et al. 1980). After derivatization with pentafluoropropionic anhydride, determinations were made using an electron captor detector. The sensitivity limit was 1 ng/ml of plasma and a coefficient of variation of 5-10% was obtained. Concentrations of the glucuronide conjugate were determined from the difference between 8-glucuronidase-hydrolysed and unhydrolysed bornaprolol concentrations. Plasma samples were incubated with 8-glucuronidase and 0 2 M sodium acetate buffer, pH 4.5, at 37°C for 16 h; optimal incubation conditions were selected after preliminary experiments. Pharrnacokinetic analysis Plasma bornaprolol concentrations were analysed by an iterative nonlinear least-squares fitting program without weighting factor (d'Athis et al. 1981). The following parameters were determined: the observed maximum plasma concentration (cmx);and the time when it appeared (tmx);the area under the plasma concentration-time curve from zero to infinity (AUC;) calculated by the trapezoydal method; the elimination half-life ( t l l l r ) calculated by regression analysis; the absolute bio-availability:
F=
AUC,"p.o.
dose i.v. X-------
AUC,"i.v.
dose oral
total body clearance:
Cl =
dose i.v. AUC," i.v.
and CI=
F .dose oral AUC; oral
and the volume of distribution ( Vdb= CI/B. For the plasma bornaprolol glucuronide only the AUC," and t,,2r were calculated. Data are expressed as mean values f SEM.
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Bornaprolol pharmacokinetics in human
857
Results Bornaprolol Concentration-time curves after i.v. and oral bornaprolol are shown in figures 1 and 2. Results of the pharmacokinetic calculations are listed in table 1. At the end of i.v. administration, plasma concentrations were of the order of 400 ng/mi. They decreased thereafter rapidly, and 8 h after injection the plasma concentration of unchanged bornaprolol was only 7 ng/ml. The t l l z Swas 2-3 h. After oral administration, peak bornaprolol concentration was reached about 1 h after the dose, and plasma drug levels were detectable for 24-48 h depending on dose. The mean t1,28was 20 h, and was independent of the oral dose. The C,,, and AUC," increased in a non-dose-dependent manner; when the dose was increased 8-fold (12&960mg), the C,, and AUC," increased by 2-7 and 4, respectively. Absolute bioavailability continued to decrease as the dose increased from 120 mg (F=0.46 kO.09) to 960mg (F=022+002). Within the dose range, and for both routes of administration, the mean C l was as high as 60 l/h. The mean value of Vdrwas also high, for both the oral route (150&20001) and the i.v. route (2001).
400
b -0
g E
9 c
-s
.-
E
c
g
s
10
E t
h 4
3 .255 35
1
2
3
4
5
6
7
8
1.1
Time after administration (h)
Figure 1 . Plasma concentrations of bornaprolol and of bornaprolol glucuronide after i.v. dosage of bomaprolol in normal human volunteers. Dose of bornaprolol was 20mg. Data are means+ SEM for six volunteers: bornaprolol(0-0); bornaprolol glucuronide (B-B); SEM values are shown as bars.
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858
G . Cheymol
w
al.
et
I I
10
J, . Im
a'
I l l
1 2 3 4 I I3
1 8
I I loii
I
I 1
20
23
'WV 47
50
71
Time after administration (h)
Figure 2.
Plasma concentrations of bornaprolol and bornaprolol glucuronide after oral dosage of bornaprolol in normal human volunteers. Dose of bornaprolol was 240mg. Data are meansf SEM for three volunteers: (0-0) bornaprolol; (W-H) bornaprolol glucuronide; SEM values are shown as bars.
Table 1. Plasma kinetic parameters for bornaprolol following single intravenous (20mg) and oral (12W960mg) doses. Doses i.v. 20 mg
c,,,
(ns/ml) (h) AUC,"(ng/ml/h) h / 2 8 (h) Cl(l/h) v,(1) t,,
F
oral 120mg
oral 240 mg
oral 480 mg
oral 960 mg
197 ( f 5 6 ) 0.8 ( + @ I ) 367 (f51) 947 (f175) 2 6 (f0-5) 186 (f4-6) 604(+9-1) 61.1 (h9-9) 207 (f90) 1514 (f422) 1 046 (f0.09)
290 (k73) 0 8 (kO.1) 1591 (+302) 208 (k5.2) 64-2 (+9-9) 2006 (f727) 040 (fO.08)
411 (f68) 0.8 (fO1) 2388 (f220) 23.8 (k4.5) 59-2 (k9-1) 2166 (f639) 029 (fO06)
528 (+135) 0.9 (fO.1) 3871 (+531) 17.7 (k3.4) 605 (k9.7) 1473 (f263) 022 ( f 0 0 2 )
Data are the means of six subjectsf SEM.
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Bornaprolol pharmacokinetics in human
859
Glucuronde conjugate The plasma pharmacokinetics of the metabolite were studied in six volunteers after i.v. administration and in three after oral administration. Figures 1 and 2 show that the conjugated derivative appeared rapidly (within 5 min after i.v. and within 10-20min after oral, doses), with the mean t,,, being about 1.5 h and 2 5 h after i.v. and oral administration, respectively. Plasma glucuronide concentrations greatly exceeded bornaprolol concentrations. The ratio of the AUC values for the glucuronide and the parent compound underlines the extent of metabolism; these were 14+_ 3 (mean f SEM) after i.v. dosage and 21 f 6, 15 f 3, 20 f7, 13f 2 in order of increasing dose for the four oral doses. The mean AUC value for the glucuronide conjugate did not increase regularly with increased oral dosage. It increased by 1.3 for doses from 120mg (19690 f9260 ng/ml per hour) to 240 mg (25260f 7860 ng/ml per hour), and by 1.9 for doses from 120mg to 480mg (37970+_11202ng/mlper hour) and plateaued at 960 mg (45760f 23400 ng/ml per hour). The rate of disappearance of glucuronide conjugate ( t I l z S= 15-20 h) was similar to that of oral bornaprolol.
Discussion The results of this study demonstrate the principal pharmacokinetic characteristics of bornaprolol. The first characteristic is the high rate of glucuronide conjugation, and the high level of metabolic elimination of bornaprolol. The glucuronide conjugated metabolite appeared in the blood very rapidly, and the ratio of the AUC values for the conjugate and the parent drug were very high after both i.v. and oral administration. These data confirmed the very low urinary excretion of the parent drug observed in preliminary investigations. Another marked characteristic of bornaprolol is its elimination tllZ (15-20 h on average) following oral administration, despite the quantitative importance of its metabolism. The discrepancy between this value and the value obtained after the i.v. dosage ( t I l z= 2-3 h) is probably due to the fact that the dose injected was much lower than oral doses, resulting in plasma drug levels detectable only over 8 h, as against the 24-48 h after oral dosage. Moreover, in another study (unpublished), bornaprolol tablets were used instead of an aqueous suspension, and the was 14.5 & 5 h for a similar range of doses. Therefore, the hypothesis of flip-flop kinetics could be ruled out. In fact, for other B-blocking agents which undergo first-pass hepatic metabolism, the t l l z is short (3 h for propranolol). Only poorly metabolized drugs (sotalol, betaxolol) have t I l 2values of 10 h or more. The tllz duration of bornaprolol can be explained by its much larger volume of distribution than that of the principal B-blockers (Giudicelli and Witchitz, 1983); this indicates marked tissue affinity. These findings can be correlated with the prolonged cardiovascular effects demonstrated in human pharmacodynamic study (Cheymol et al. 1987). A further characteristic is the nonlinearity of the pharmacokinetics within the range of oral doses used. When doses were increased from 1 to 8, the AUC and Cmx values increased in smaller proportions (by 4 and 2.8, respectively). Assuming that clearance remained constwt within the range of doses, calculation showed that F decreased when oral doses &-creased. This does not appear to correspond to a dosedependent increase in metabolism. If this were the case we would observe an increase
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860
Bornaprolol pharmacokinetics in human
in the ratio of the AUC values of the glucuronide conjugate and the parent compound. In the present study this ratio did not change significantly with increased dosage. Therefore, we propose the hypothesis that intestinal absorption becomes saturated as bornaprolol dosage is increased. Propranolol is the usual reference product for j?-blockers which are eliminated mainly after metabolism. Bornaprolol differs from propranolol, primarily in the quantitative importance of the metabolic process, and in its nonlinear pharmacokinetic behaviour. Several authors have reported that propranolol follows first-order kinetics following single oral administration for doses ranging from 40 to 160mg; linearily disappears only at lower oral doses. The explanation for this is that the metabolizing enzymes of the liver may become saturated (Borgstrom et al. 1981, Zopitar et al. 1986). Moreover according to Walle et al. 1979, the AUC value of propranolol glucuronide is similar to that of the parent drug after i.v. administration, and it only exceeds this by a factor of 7 after oral dose. As for bornaprolol, the metabolite/parent compound AUC ratio was clearly higher, after both i.v. and oral route. In conclusion, bornaprolol is a fl-blocking agent eliminated mainly by metabolism, with a bioavailability that decreases inversely with oral dose. The persistence of its pharmacological effects, could be related to its long elimination t 1 , 2 .
Acknowledgements The authors would like to express their gratitude to Dr J. Barrk for suggestions and comments.
References BERNARD, N., CUISINAUD, G., JOZEFCZAK, C., SECCIA, M., FERRY, N., and SASSARD, J., 1980,Sensitive gas chromatographicmethod for the determination in plasma of FM 24,1-(2-exo-bicyclo[2,2,l]hept2-ylphenoxy)-3-[(1 -methylethyl amino12-propano1,a new /?-adrenoceptorblocking agent. Journal of Chromatography, 183, 99-103. BORGSTROM, L., JOHANSSON, C.-G., LARSSON,H., and LENANDER, R., 1981, Pharmacokinetics of propranolol. Journal of Pharmacokinetics and Biopharmaceutics, 9, 419429. CHEYMOL, G., JAILLON, P., LECOQ, V., CHEYMOL, A,, and KRUMENACKER, M., 1987,Cardiovascular b&aadrenergic blocking effects of bornaprolol in man; relationship to dose and plasma concentration. Journal of Cardiowascular Pharmacology, 9, 694-698. D’ATHIS, P. H., RICHARD, M.-O., DE LAUTURE, D., REY,E., BOWIER-D’YVOIRE, M., C L~ M ENE., T,and OLIVE,G., 1981, Etude comparative des biodisponibilitks de deux formes de spironolactone. Thirapie, 36,443-449. GIUDICELLI, J . F., and WITCHITZ, S.,1983, Les bita-bloquants. Semaine des H6Pitauc, Park, 34, 2395-2426. LE FUR,G., CANTON, T., MALGOURIS, C., PAILLARD, J.J., HARDY, J. C., GUEREMY, C., and UZAN,A., 1981,Stereospecificity of the in witro and in oliwo blockade of B-receptors by FM 24, a slowly reversible ligand. Life Sciences, 29, 2481-2489. LEFUR,G., PAILLARD, J. J., ROUGEOT, C., and UZAN, A,, 1980,Tissue levels and displacement of in wiwo labelled /?-adrenergic receptors by FM 24, an irreversible or slowly dissociable /?-blocker. European Journal of Pharmacology, 67,413418. LE FUR,G., SCHMELCK, PH., GEYNET, P., HANOUNE, J., and U Z ~ NA., , 1978,Cardiac beta-adrenergic receptor: evaluation of FM 24 as a new and very slowly dissociable blocker. Life Sciences, 23, 1841-1 850. MESTRE, M., LE FUR,G., and UZAN,A., 1978, Long acting effect of 1-2-(exo-bicyclo[2,2,l]hept-2y1phenoxy)-3-[(1 -methylethyl)amino]-2-propanol hydrochloride (FM 24), a new /?-blocking agent. Proceedings, 7th International Congress of Pharmacology, I U P H A R (Oxford: Pergamon Press), Abstr, 2912,p. 961. WALLE, T.,FAGAN, T.-C., CONRADI, E.-C., WALLE, U.-K., and GAFFNEY, T.-E., 1979,Presystemic and systemic glucuronidation of propranolol. Clinical Pharmacology and Therapeutics, 26, 167-1 72. ZOPITAR, Z., VRHOVA, B., LENARDI~, A,, CVELBAR, P., 2 0 ~ 2M., , and FRANCETIC, I., 1986, Dosedependent bioavailability of propranolol. International Journal of Clinical Pharmacology, 24, 319-322.
ISSN: 0049-8254 (Print) 1366-5928 (Online) Journal homepage: http://www.tandfonline.com/loi/ixen20
Pharmacokinetic characteristics of bornaprolol in healthy volunteers G. Cheymol, A. Cheymol, C. Jozefczak, V. Lecoq, B. Lecoq & P. Jaillon To cite this article: G. Cheymol, A. Cheymol, C. Jozefczak, V. Lecoq, B. Lecoq & P. Jaillon (1990) Pharmacokinetic characteristics of bornaprolol in healthy volunteers, Xenobiotica, 20:8, 855-860 To link to this article: http://dx.doi.org/10.3109/00498259009046899
Published online: 27 Aug 2009.
Submit your article to this journal
Article views: 4
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ixen20 Download by: [University of California Santa Barbara]
Date: 06 November 2015, At: 05:26
XENOBIOTICA,
1990, VOL. 20,
NO.
8, 855-860
Pharmacokinetic characteristics of bornaprolol in healthy volunteers G. CHEYMOLtS, A. CHEYMOL, C. JOZEFCZAKg, V. LECOQT, B. LECOQT and P. JAILLONT Downloaded by [University of California Santa Barbara] at 05:26 06 November 2015
t Service de Pharmacologie, H6pital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012, Paris, France § Phamuka Laboratories, Gennevilliers, France 7 Unit6 de Pharmacologie Clinique, H6pital Saint-Antoine, Paris, France
Received 15 July 1988; accepted 21 April 1990 1. Six young male volunteers received five single doses of bornaprolol, i.v. (20 mg) and orally (120, 240,480,960 mg) administered at 2-week intervals. Plasma concentrations of bornaprolol and its conjugated metabolite were determined by gas chromatography. 2. After i.v. administration, plasma bornaprolol levels were detectable over 8 h, and mean values were 60 l/h for total clearance (Cl), 207 1 for volume of distribution ( Vs),2 6 h for elimination half-life (tl12#). After oral administration, plasma bornaprolol levels were detectable over 24-48 h, and mean values of pharmacokinetics parameters were 601/hfor C1,1500 1for Vr,20 h for t1,*#.Maximum plasma concentrations and area under the plasma concentration-time curve increased in a non-dose-dependent manner. 3. The glucuronide conjugate appeared in the blood within 5-l0min and its plasma level greatly exceeded bornaprolol concentrations. The mean value of the ratio of the metabolite AUC/parent product AUC was 14 after i.v. administration and 13-21 following oral administration, depending on dose. The AUC for the metabolite did not increase proportionally with oral doses. 4. Bornaprolol is principally eliminated after metabolism. This process did not increase with increasing oral doses and bioavailability seemed to decrease inversely with oral dose.
Introduction Bornaprolol, a norbornyl derivative, is a new, non-cardioselective /?-blocker, possessing prolonged /?-adrenergic antagonistic activity on receptors in vitro and in vivo. In vitro, bornaprolol inhibits isoproterenol-inducedstimulation of adenylate cyclase in rat heart homogenate; this inhibition was apparently non-dissociable since it could not be reversed either by addition of an excess of isoproterenol, or by washing (Le Fur et al. 1978). In mice, bornaprolol induced durable blockade of /3receptors in the heart, brain and lungs (Le Fur et al. 1980). In conscious dogs, bornaprolol was equipotent to propranolol on isoproterenol-induced tachycardia, but its duration of action was 2-3 times longer (Mestre et 01.1978). This prolonged inhibition could not be correlated with tissue levels of labelled bornaprolol, and appeared to be related to very slow dissociable binding to /?-receptors(Le Fur et al. 1980, 1981). The results of a study after single oral administration to healthy volunteers confirmed data obtained in animals (Cheymol et af. 1987). Bornaprolol induced prolonged cardiovascular/?-blockade,the duration of which depended on dosage and type of protocol, namely from 24 h (120-240 mg bornaprolol) to 48 h (480-960 mg) for hypertension and exercise-induced tachycardia, and over 72 h for isoproterenolinduced tachycardia (80, 160, 240mg). $ T o whom correspondence should be addressed. M)49-8254)90 S3.W 0 1990 Taylor 8z Francis Ltd.
856
G. Cheymol et al.
Preliminary investigations in dogs and man have shown low plasma levels of unchanged drug and high concentrations of the glucuronide conjugate, associated with low urinary excretion of the parent drug, equivalent to less than 1% of oral and i.v. doses administered (A. Uzan 1986, personal communication). The objective of the present study was to determine the plasma pharmacokinetic characteristics of bornaprolol in health volunteers.
Downloaded by [University of California Santa Barbara] at 05:26 06 November 2015
Subjects and methods Subjects The study was carried out in healthy male volunteers (age 26-34 years, weight 60-80 kg, height 17Ck 190cm), who had previously undergone a physical examination and laboratory tests to exclude subjects presenting any contraindication to 8-blockers. All gave their informed consent to participate in the study, and were not taking medication. The protocol was approved by the ethics committee of the Saint-Antoine hospital. Drug Bornaprolol is (+)-1-(2-exo-bicyclo [2,2,l]hept-2-ylphenoxy)-3-[(l-methylethyl)amino]-2propanol hydrochloride (50 :50 mixture of the two racemic diastereoisomers).
Plasma kinetics Single intravenous (20mg) and oral doses (120, 240, 480, 960mg) of bornaprolol were given to six subjects. Doses were administered at 2-week intervals, in the morning after an overnight fast, followed 2 h later by a light breakfast. For oral administration, the product was taken as an aqueous suspension. Blood pressure and heart rate were monitored during the study. After oral administration, blood samples were nd collectedat 10,20,30,45min, 1 , 1 ~ 5 , 2 , 2 ~ 5 , 3 , 4 , 5 , 6 , 8 , 1 0 , 1 1 , 2 3 , 4 7 , 7 1 , 9 5 , 1 1 9 , 1 4 3 a 167h.Afteri.v. administration, additional samples were collected during the first 10 min. Plasma samples were stored at - 20°C until assay. Assays Plasma concentrations of bornaprolol and its glucuronide conjugated were determined by g.1.c. (Bernard et al. 1980). After derivatization with pentafluoropropionic anhydride, determinations were made using an electron captor detector. The sensitivity limit was 1 ng/ml of plasma and a coefficient of variation of 5-10% was obtained. Concentrations of the glucuronide conjugate were determined from the difference between 8-glucuronidase-hydrolysed and unhydrolysed bornaprolol concentrations. Plasma samples were incubated with 8-glucuronidase and 0 2 M sodium acetate buffer, pH 4.5, at 37°C for 16 h; optimal incubation conditions were selected after preliminary experiments. Pharrnacokinetic analysis Plasma bornaprolol concentrations were analysed by an iterative nonlinear least-squares fitting program without weighting factor (d'Athis et al. 1981). The following parameters were determined: the observed maximum plasma concentration (cmx);and the time when it appeared (tmx);the area under the plasma concentration-time curve from zero to infinity (AUC;) calculated by the trapezoydal method; the elimination half-life ( t l l l r ) calculated by regression analysis; the absolute bio-availability:
F=
AUC,"p.o.
dose i.v. X-------
AUC,"i.v.
dose oral
total body clearance:
Cl =
dose i.v. AUC," i.v.
and CI=
F .dose oral AUC; oral
and the volume of distribution ( Vdb= CI/B. For the plasma bornaprolol glucuronide only the AUC," and t,,2r were calculated. Data are expressed as mean values f SEM.
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Bornaprolol pharmacokinetics in human
857
Results Bornaprolol Concentration-time curves after i.v. and oral bornaprolol are shown in figures 1 and 2. Results of the pharmacokinetic calculations are listed in table 1. At the end of i.v. administration, plasma concentrations were of the order of 400 ng/mi. They decreased thereafter rapidly, and 8 h after injection the plasma concentration of unchanged bornaprolol was only 7 ng/ml. The t l l z Swas 2-3 h. After oral administration, peak bornaprolol concentration was reached about 1 h after the dose, and plasma drug levels were detectable for 24-48 h depending on dose. The mean t1,28was 20 h, and was independent of the oral dose. The C,,, and AUC," increased in a non-dose-dependent manner; when the dose was increased 8-fold (12&960mg), the C,, and AUC," increased by 2-7 and 4, respectively. Absolute bioavailability continued to decrease as the dose increased from 120 mg (F=0.46 kO.09) to 960mg (F=022+002). Within the dose range, and for both routes of administration, the mean C l was as high as 60 l/h. The mean value of Vdrwas also high, for both the oral route (150&20001) and the i.v. route (2001).
400
b -0
g E
9 c
-s
.-
E
c
g
s
10
E t
h 4
3 .255 35
1
2
3
4
5
6
7
8
1.1
Time after administration (h)
Figure 1 . Plasma concentrations of bornaprolol and of bornaprolol glucuronide after i.v. dosage of bomaprolol in normal human volunteers. Dose of bornaprolol was 20mg. Data are means+ SEM for six volunteers: bornaprolol(0-0); bornaprolol glucuronide (B-B); SEM values are shown as bars.
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858
G . Cheymol
w
al.
et
I I
10
J, . Im
a'
I l l
1 2 3 4 I I3
1 8
I I loii
I
I 1
20
23
'WV 47
50
71
Time after administration (h)
Figure 2.
Plasma concentrations of bornaprolol and bornaprolol glucuronide after oral dosage of bornaprolol in normal human volunteers. Dose of bornaprolol was 240mg. Data are meansf SEM for three volunteers: (0-0) bornaprolol; (W-H) bornaprolol glucuronide; SEM values are shown as bars.
Table 1. Plasma kinetic parameters for bornaprolol following single intravenous (20mg) and oral (12W960mg) doses. Doses i.v. 20 mg
c,,,
(ns/ml) (h) AUC,"(ng/ml/h) h / 2 8 (h) Cl(l/h) v,(1) t,,
F
oral 120mg
oral 240 mg
oral 480 mg
oral 960 mg
197 ( f 5 6 ) 0.8 ( + @ I ) 367 (f51) 947 (f175) 2 6 (f0-5) 186 (f4-6) 604(+9-1) 61.1 (h9-9) 207 (f90) 1514 (f422) 1 046 (f0.09)
290 (k73) 0 8 (kO.1) 1591 (+302) 208 (k5.2) 64-2 (+9-9) 2006 (f727) 040 (fO.08)
411 (f68) 0.8 (fO1) 2388 (f220) 23.8 (k4.5) 59-2 (k9-1) 2166 (f639) 029 (fO06)
528 (+135) 0.9 (fO.1) 3871 (+531) 17.7 (k3.4) 605 (k9.7) 1473 (f263) 022 ( f 0 0 2 )
Data are the means of six subjectsf SEM.
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Bornaprolol pharmacokinetics in human
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Glucuronde conjugate The plasma pharmacokinetics of the metabolite were studied in six volunteers after i.v. administration and in three after oral administration. Figures 1 and 2 show that the conjugated derivative appeared rapidly (within 5 min after i.v. and within 10-20min after oral, doses), with the mean t,,, being about 1.5 h and 2 5 h after i.v. and oral administration, respectively. Plasma glucuronide concentrations greatly exceeded bornaprolol concentrations. The ratio of the AUC values for the glucuronide and the parent compound underlines the extent of metabolism; these were 14+_ 3 (mean f SEM) after i.v. dosage and 21 f 6, 15 f 3, 20 f7, 13f 2 in order of increasing dose for the four oral doses. The mean AUC value for the glucuronide conjugate did not increase regularly with increased oral dosage. It increased by 1.3 for doses from 120mg (19690 f9260 ng/ml per hour) to 240 mg (25260f 7860 ng/ml per hour), and by 1.9 for doses from 120mg to 480mg (37970+_11202ng/mlper hour) and plateaued at 960 mg (45760f 23400 ng/ml per hour). The rate of disappearance of glucuronide conjugate ( t I l z S= 15-20 h) was similar to that of oral bornaprolol.
Discussion The results of this study demonstrate the principal pharmacokinetic characteristics of bornaprolol. The first characteristic is the high rate of glucuronide conjugation, and the high level of metabolic elimination of bornaprolol. The glucuronide conjugated metabolite appeared in the blood very rapidly, and the ratio of the AUC values for the conjugate and the parent drug were very high after both i.v. and oral administration. These data confirmed the very low urinary excretion of the parent drug observed in preliminary investigations. Another marked characteristic of bornaprolol is its elimination tllZ (15-20 h on average) following oral administration, despite the quantitative importance of its metabolism. The discrepancy between this value and the value obtained after the i.v. dosage ( t I l z= 2-3 h) is probably due to the fact that the dose injected was much lower than oral doses, resulting in plasma drug levels detectable only over 8 h, as against the 24-48 h after oral dosage. Moreover, in another study (unpublished), bornaprolol tablets were used instead of an aqueous suspension, and the was 14.5 & 5 h for a similar range of doses. Therefore, the hypothesis of flip-flop kinetics could be ruled out. In fact, for other B-blocking agents which undergo first-pass hepatic metabolism, the t l l z is short (3 h for propranolol). Only poorly metabolized drugs (sotalol, betaxolol) have t I l 2values of 10 h or more. The tllz duration of bornaprolol can be explained by its much larger volume of distribution than that of the principal B-blockers (Giudicelli and Witchitz, 1983); this indicates marked tissue affinity. These findings can be correlated with the prolonged cardiovascular effects demonstrated in human pharmacodynamic study (Cheymol et al. 1987). A further characteristic is the nonlinearity of the pharmacokinetics within the range of oral doses used. When doses were increased from 1 to 8, the AUC and Cmx values increased in smaller proportions (by 4 and 2.8, respectively). Assuming that clearance remained constwt within the range of doses, calculation showed that F decreased when oral doses &-creased. This does not appear to correspond to a dosedependent increase in metabolism. If this were the case we would observe an increase
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Bornaprolol pharmacokinetics in human
in the ratio of the AUC values of the glucuronide conjugate and the parent compound. In the present study this ratio did not change significantly with increased dosage. Therefore, we propose the hypothesis that intestinal absorption becomes saturated as bornaprolol dosage is increased. Propranolol is the usual reference product for j?-blockers which are eliminated mainly after metabolism. Bornaprolol differs from propranolol, primarily in the quantitative importance of the metabolic process, and in its nonlinear pharmacokinetic behaviour. Several authors have reported that propranolol follows first-order kinetics following single oral administration for doses ranging from 40 to 160mg; linearily disappears only at lower oral doses. The explanation for this is that the metabolizing enzymes of the liver may become saturated (Borgstrom et al. 1981, Zopitar et al. 1986). Moreover according to Walle et al. 1979, the AUC value of propranolol glucuronide is similar to that of the parent drug after i.v. administration, and it only exceeds this by a factor of 7 after oral dose. As for bornaprolol, the metabolite/parent compound AUC ratio was clearly higher, after both i.v. and oral route. In conclusion, bornaprolol is a fl-blocking agent eliminated mainly by metabolism, with a bioavailability that decreases inversely with oral dose. The persistence of its pharmacological effects, could be related to its long elimination t 1 , 2 .
Acknowledgements The authors would like to express their gratitude to Dr J. Barrk for suggestions and comments.
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