Br. J. clin. Pharmac. (1979), 7, 89-93
PHARMACOKINETICS OF PROPANTHELINE BROMIDE IN NORMAL MAN C.W. VOSE, G.C. FORD, S.J.W. GRIGSON, N.J. HASKINS, M. PROUT, P.M. STEVENS, D.A. ROSE & R.F. PALMER Department of Metabolic Studies, G.D. Searle and Co. Ltd, Land End Road, High Wycombe, Bucks HP12 4HL H. RUDEL Asociacion de Investigacion, Farmacologica Mexicana A.C., Medellin No. 273, Mexico 7 DF
I Six normal men were administered propantheline bromide (15 mg) in single doses intravenously, and as an oral solution in a balanced random crossover study. 2 Plasma concentrations and urinary excretion of the drug were measured after each treatment, using a stable isotope dilution assay. 3 Initial plasma concentrations of propantheline bromide ranged from 494 to 1310 ng ml-' 3 min after the intravenous dose. Plasma levels of the drug decreased rapidly to reach concentrations of 4.5 to 27.2 ng ml-' 4 h after dosage. A total of 17.3% (range 8.73 to 23.69%) of the intravenous propantheline bromide was eliminated by excretion in urine. 4 Pharmacokinetic analysis of these data indicated mean biological half-lives of 3.2 min (range 1.2 to 4.2 min; distribution phase) 57.9 min (range 12.6 to 106.2 min; fast elimination phase) and 2.93 h (range 2.16 to 3.69 h; slow elimination phase). 5 Total plasma clearance was calculated as 79.2 1 h-' (range 28.1 to 137.7 1 h-1) and the renal clearance was 11.5 1 h-' (range 6.7 to 15.71 h-') demonstrating the importance of extra-renal routes in the elimination of propantheline bromide. 6 Following the oral dose of propantheline bromide plasma concentrations of the drug were at or below the precision level of the assay (5 ng ml-') at all times after dosage. A total of 1.08% (range 0.33 to 2.05%) of the propantheline bromide administered was excreted in urine. 7 The results of this study show that propantheline bromide was rapidly distributed and eliminated in man, and that extra-renal routes (probably metabolism) were the major pathways of elimination. Comparison of the data obtained following oral and intravenous administration indicate a low systemic availability of orally administered propantheline bromide. This may reflect the importance of the extra-renal routes of elimination in a 'first-pass' effect for the drug.
Introduction
Propantheline bromide [Figure la, (2-hydroxyethyl) di-isopropylmethylammonium bromide xanthene-9carboxylatel is a quaternary ammonium compound possessing anticholinergic properties, used for some years in the treatment of peptic ulcer and renal colic. This compound appears to undergo appreciable metabolism in man, even after intravenous administration (Beermann, Hellstrom & Rosen, 1972). Following oral administration of "4C-labelled propantheline bromide to normal men some 70% of the administered radioactivity was excreted in urine, but the majority of this was present as metabolites of the drug (Beermann et al., 1972; Vose, Prout, Haskins, Ford, Palmer &
Tidd, 1978). These metabolites included xanthanoic acid, hydroxyxanthanoic acid, hydroxypropantheline, and a number of conjugates. While the metabolism of this drug has been studied, little is known about its pharmacokinetics. This reflects the difficulty in quantifying propantheline bromide in biological fluids. A spectrophotometric method (Pfeffer, Schar, Bolton & Jacobsen, 1968) and a fluorimetric method (Westerlund & Karset, 1970), utilizing ion pair extraction techniques, have been reported. However, these did not have the necessary sensitivity to measure low concentrations of propantheline bromide. Recently a more sensitive and specific assay for
90
C.W. VOSE ETAL.
The present report .describes the application of this sensitive assay to a study of the -plasma concentrations and urinary -.excretion of propantheline bromide in normal} man following single intravenous and oral doses of the compound, and provides some pharmacokinetic data not previously available for this compound.
CH (CH3 )2
.1I
COCH2 CH2N-C4(CH3 )2
Br 0
a R=-CH3 b R=CD3
Methods
Figure 1 Chemical-structures of (a) propantheline bromide and (b) deuterium labelled propantheline
bromide.
propantheline bromide in. urine and plasma has been developed in these laboratories -(Ford, Guigson, -Haskins, Palmer, Prout & Vose,. 1977). This allows the compound.to be accurately.quantified in these biological fluids, with a quantitation. limit of about 5 ng ml-'. This assay uses the deuterium labelled compound (Figure lb) as te.i.trnal stadard, and multiple ion monitoring to --measure propantheline bromide in biological fluids by gas chromatography-mass spectrometry.
-
Propanthlfine bromide was obtained from Searle de Mexico, S.A. de C.V., Mexico City. The intravenous dosage was prepared by dissolving propantheline bromide (15-.mg) in sterile 0.9% saline (5 ml), and the oral -solution was prepared by dissolving the drug (15 mg) in distilled water (150 ml), immediately prior to dosage.
Clinical procedure The subjects weresix-..normal men aged 21-24-years who had given informed consent tQ participate in the study, and were judged healthy by a medical and
Table 1 P-Plasrs conce*etions (ng mf-1) of propantheline brQmide following a sinle intravenourdose
Time (min) 3 5
10 15
130 60 90
120 150 180 240
R{;
.JZ
1231 665 333 1 67 145 -38.0 26.0 0 0 0 0
786 457 *208 J28 067.2 .-36.6 27-2 24.2 31.7 :22.6 14#3
VP
*896 534 -249 192 102
6&8 33.2 28.3 24.2 18.9
15;8
Subject V)
1310 924 , 499 329 171 93.2 -Q0.0 37.7 44.5 29.1 : 27.2
JG
*494 285
440
97.0 *-45.0 20.0 -25.0 14.0 4.1 4.5 0
RH
Mean
.544 308 142 *72.5 40.0
876.8 528.8 261.8 164.3 95.0 45.8 31.2 19.9 19.3 14.2 10.6
20.0
16.0 15.0 1 tO 10.0 6,0
TabI2 Half-i and cWarancofintravenoupropanthelinebroaodde Su*ct
T.{ (min)
Tjb-(Mln)
RG
3.6 -3.6 1.2 3.0 -42
49.2 106.2 12.6
Jz
VP VD JG FRH Mean
'3.6
:3.2
qT-
c(hJ
1 9t8
2.16 3.69
54105.0 57:9
2.93
'
a'Distributiowtphase; b'Fet' eNrninetin phase; c 'SloW elimination pbase
Plasma cleauce 1 h-1)
Total
Renal
66.2 6&.3 53.4
13.6 15.7 10.0 6.7 12.0
28.1 137.7 121.2 79.2
*10.9 11.5
PROPANTHELINE BROMIDE PHARMACOKINETICS
biochemical pre-trial screen. The subjects fasted and abstained from all liquids for 10 h prior to dosage, except for the ingestion of 200 ml water 1 h before dosage. The subjects were forbidden alcohol from 24 h before dosing until sample collection was completed for each experiment, and all forms of medication were forbidden from 2 weeks before the study until its completion. A 1 week wash-out interval was allowed between each pha-se of the study. On the morning of dosing each volunteer received propantheline bromide (15 mg), intravenously, or as an oral solution in water (150 ml) in a balanced random crossover. The intravenous administration of the drug was carried out at a constant rate over 2.5 min. Urine samples were collected for 12 h before dosage and during 0-2, 2-4, 4-6, 6-8, 8-12, 12-24, 24-48, 48-72 and 72-96 h after dosage, into vessels containing 1 M perchioric acid (10 ml), and stored frozen at -200C. Blood samples (10 ml) were obtained from an antecubital vein immediately before dosage, and at 3*, 5* (* these samples were taken only after the intravenous dose), 10, 15, 30 and 60 min, and 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24,27, 30,48, 72 and 96 h after dosage. Each blood sample was immediately transferred to a heparinised tube, acidified, centrifuged, and the separated plasma was added to an equal volume of 0.1 M perchloric acid and frozen at - 200C within one hour of collection. Extraction and analysis of propantheline bromide in plasma and urine An aliquot of each urine sample (10 ml) and each acidified plasma sample (5 ml, equivalent to 2.5 ml of plasma) was extracted and analyzed by the method described previously (Ford et al, 1977). Table 3 Mean cumulative urinary excretion of propantheline bromide in 48 h following intravenous and oral administration of the drug Subject
RG Jz
VP VD JG
Rt Mean
% dose of propanthetne bromide excreted as intact drug Intravenoua
Oral
20.50 23.02 18.81 23.69 8.73 8.96 17.3
0.33 1.90
0.60 2.05
0.50
0.54 1.08
* Urine collections wer obtained only up to 12 h after dosage, this value not included in calcuating
mean value
91
Pharmacokinetic analysis of the plasma concentration and urinary excretion data was made using Metzler's NONLIN programme. Results In all six subjects propantheline bromide was rapidly cleared from plasma after intravenous administration (Table 1). The mean concentration decreased rapidly from 876.8 ng ml-l (range 494-1310 ng ml-') at 3 min after dosage, to 95 ngml-l (range 40.0-171.0ngml-') 30min after the i.v. dose. Thereafter the plasma levels of propantheline bromide decreased more slowly to 10.6 ng ml-' (range 0 to 27.2 ng ml-') at 4 h after administration. At all subsequent sampling times plasma concentrations of the drug were below the level of accurate quantitation (5 ng ml-'). In four of the subjects the plasma levels of propantheline bromide exhibited a biphasic decline, whereas in the other two subjects a third phase could be resolved. The half-lives of these phases are listed in Table 2 with other pharmacokinetic parameters. The initial (distribution) phase had a half-life of 3.2 min (range 1.2-4.2 min) and the second ('fast' elimination) phase had a half-life of 57.9 mm (range 12.6-106.2 min). The third ('slow' elimination) phase observed for subjects VP and VD had a half-life of 2.16 and 3.69 respectively. Following the oral dose of propantheline bromide plasma levels were very low, at or below the precision level of the assay (5 ng ml-') at all times after administration, and could not be accurately measured. The cumulative urinary excretion data listed in Table 3 showed that 17.3% (range 8.73-23.69%) of the intravenous propantheline bromide was excreted in urine. However, only 1.08% (range 0.33-2.05%) of the oral dose was eliminated by this route. The majority of the urinary excretion occurred in the first 8 h regardless of the route of administration. From the plasma concentrations and the urinary excretion data the plasma clearances of intravenous propantheline bromide were calculated (Tabe 2). There was a large inter-individual variation in the total plasma clearance, which ranged from 28.11 kh-I in 137.71 ' in subject 1G. In contms subject VD to there was a much smaller inter-individual variation in the plasma renal clearance from 6.7 to 15.7 1 h-l. During the study subjective observations of pharmacological effects of propantheline -bromide were reported by the subjects. Thus, following the oral dose they reported a deecree in salvary secretion, reflected by a dry mouth. This effect qieared between 30 and 6Gmi after dosage and lasted for a furthr I to 3 h. Following the intravenous doae this dry mouth sensation developed more rapidly, in some cases within a few minutes, and was of higher intensity and longer daration. In addition uriary hesitancy was
92
C.W. VOSE ETAL.
observed tbolowimg the i.v. dose, and was reflected by the absence of urine samples for the first 3 or 4 collection periods in some of the volunteers.
Discussion The rapid disappearance of intravenously administered propantheline bromide from plasma demonstrates a fast distribution and elimination of this drug in man. The half-lives of the phases associated with the decline in the plasma concentration of propantheline bromide are similar to those reported for a number of other quaternary ammonium compounds (Calvey, Williams, Muir & Barber, 1976; Scoular, Monks, Burgess & Turner, 1977). The very low plasma concentrations of propantheline bromide achieved after oral administration precluded their accurate measurement, and so no estimate of the rate of absorption could be obtained. This plasma level data, and the low urinary excretion of the orally administered drug indicated a low systemic availability, about 6.2% based on the mean cumulative urinary excretion data. This may account for the observed therapeutic ratio of the drug when given orally and parenterally (Moller & Rosen, 1968). Low plasma levels of orally administered propantheline bromide have been reported previously by Westerlund & Karset (1970), who found plasma levels of the drug were below 40 ng ml-" (the precision level of their assay) at all times after a 30 mg oral dose. The urinary excretiot of propantheline bromide observed in the present study following its intravenous and oral administration are similar to those reported by Beermann et al. (1972) in a study of a radiolabelled form of the compound. The mean plasma clearance data collected in the present study demonstrates a high total plasma clearance of propantheline bromide, 79.2 1 h-' (range 28.1-137.7 1 h-1). However, the renal clearance of the drug was low, 11.5 1 h-1 (range 6.7-15.7 1 h-1). Thus, urinary excretion is a minor route of elimination for propantheline bromide in man, the major routes of elimination being extra-renal. Since propantheline bromide is known to be appreciably metabolized after
intravenous administration (Beermann et al., 1972) this high extra-renal clearance probably reflects the importance of metabolism in the elimination of the drug. The inter-individual variation in the plasma renal clearance was low whereas the variation in total clearance was large. This suggests that the major source of inter-individual variation in the pharmacokinetics and pharmacology of propantheline bromide is the inter-individual difference in the extra-renal clearance of the drug. The apparently low systemic availability of orally administered drug observed in the present study has been reported previously (Beermann et al., 1972) from studies using carbon-14 labelled propantheline bromide. These workers suggested that this low availability reflected the enzymatic hydrolysis of the drug in the gastro-intestinal lumen and the poor absorption of quaternary ammonium compounds (Levine & Pelikan, 1964). However, the present study indicates that extra-renal routes, probably metabolism as discussed above, are the major pathways of elimination of propantheline bromide. Thus the low systemic availability of this compound may also result from a 'first pass' metabolism of the absorbed drug following oral administration. Although the present study indicates a low availability of oral propantheline bromide there is good evidence of its pharmacological activity in man (Moller & Rosen, 1968; Gibaldi & Grundhofer, 1975). These workers demonstrated a dose related suppression of salivary secretion with increasing oral doses of propantheline bromide. Since for most anticholinergics suppression of salivary secretion reflects the suppression of gastric secretion (Ivey, 1975) these studies provide evidence of the effectiveness of orally administered propantheline bromide. Further evidence of the pharmacological activity of this drug after oral administration was provided in the present study by the subjective observation of anticholinergic side effects in men having very low plasma levels of propantheline bromide. The pharmacokinetic data described in the present report may be of value in further studies on propantheline bromide and in studies of the relationship between blood levels and pharmacological activity.
References BEERMANN, B., HELLSTROM, K. & ROSEN, A. (1972). On.
the metabolism of propantheline in man. Clin. Pharmac. Ther., 13,212-220.
CALVEY, T.N., WILLIAMS, N.E., MUIR, K.T. & BARBER,
H.E. (1976). Plasma concentration of edrophonium in man. Clin. Pharmac. Ther., 19,813-820. FORD, G.C., GRIGSON, SJ.W., HASKINS, NJ., PALMER,
R.F., PROUT, M. & VOSE, C.W. (1977). Measurement of propantheline ion in biological fluids after administering
propantheline bromide to man. Biomed. Mass Spectrom., 4, 94-97. GIBALDI, M. & GRUNDHOFER, B. (1975). Biopharmaceutic influences on the anticholinergic effects of propantheline. Clin. Pharmac. Ther., 18, 457-461. IVEY, K. (1975). Anticholinergics: Do they work? Gastroenterology, 68, 154-166. LEVINE, R.R. & PELIKAN, E.A. (1964). Mechanisms of drug absorption and excretion. Ann. Rev. Pharmac., 4, 69-84.
PROPANTHELINE BROMIDE PHARMACOKINETICS MOLLER, J. & ROSEN, A. (1968). Comparative studies on intramuscular and oral effective doses of some anticholinergic drugs. Acta Med. Scand., 184, 201-209. PFEFFER, M., SCHAR, J.M., BOLTON, S. & JACOBSEN, R.
(1968). Human urinary excretion of quaternary ammonium compounds anisotropinemethyl bromide and propantheline bromide. J. pharm. Sci., 57, 1375-1379. SCOULAR, I.T., MONKS, A., BURGESS, C. & TURNER, P.
(1977). Human studies of the bioavailability of a quaternary ammonium compound, tiemonium bromide and tiemonium methosulphate. Curr. med. Res. Opin., 4, 732-738.
93
VOSE, C.W., PROUT, M., HASKINS, NJ., FORD, G.C.,
PALMER, R.F. & TIDD, MJ. (1978). Identification of some urinary metabolites of propantheline bromide. Xenobiotica (in press). WESTERLUND, D. & KARSET, K.H. (1970). Fluorimetric determination of propantheline in human blood plasma by an ion pair extraction method. Acta Pharin. Suecica., 7, 267-278.
(Received December 21, 1977)
PHARMACOKINETICS OF PROPANTHELINE BROMIDE IN NORMAL MAN C.W. VOSE, G.C. FORD, S.J.W. GRIGSON, N.J. HASKINS, M. PROUT, P.M. STEVENS, D.A. ROSE & R.F. PALMER Department of Metabolic Studies, G.D. Searle and Co. Ltd, Land End Road, High Wycombe, Bucks HP12 4HL H. RUDEL Asociacion de Investigacion, Farmacologica Mexicana A.C., Medellin No. 273, Mexico 7 DF
I Six normal men were administered propantheline bromide (15 mg) in single doses intravenously, and as an oral solution in a balanced random crossover study. 2 Plasma concentrations and urinary excretion of the drug were measured after each treatment, using a stable isotope dilution assay. 3 Initial plasma concentrations of propantheline bromide ranged from 494 to 1310 ng ml-' 3 min after the intravenous dose. Plasma levels of the drug decreased rapidly to reach concentrations of 4.5 to 27.2 ng ml-' 4 h after dosage. A total of 17.3% (range 8.73 to 23.69%) of the intravenous propantheline bromide was eliminated by excretion in urine. 4 Pharmacokinetic analysis of these data indicated mean biological half-lives of 3.2 min (range 1.2 to 4.2 min; distribution phase) 57.9 min (range 12.6 to 106.2 min; fast elimination phase) and 2.93 h (range 2.16 to 3.69 h; slow elimination phase). 5 Total plasma clearance was calculated as 79.2 1 h-' (range 28.1 to 137.7 1 h-1) and the renal clearance was 11.5 1 h-' (range 6.7 to 15.71 h-') demonstrating the importance of extra-renal routes in the elimination of propantheline bromide. 6 Following the oral dose of propantheline bromide plasma concentrations of the drug were at or below the precision level of the assay (5 ng ml-') at all times after dosage. A total of 1.08% (range 0.33 to 2.05%) of the propantheline bromide administered was excreted in urine. 7 The results of this study show that propantheline bromide was rapidly distributed and eliminated in man, and that extra-renal routes (probably metabolism) were the major pathways of elimination. Comparison of the data obtained following oral and intravenous administration indicate a low systemic availability of orally administered propantheline bromide. This may reflect the importance of the extra-renal routes of elimination in a 'first-pass' effect for the drug.
Introduction
Propantheline bromide [Figure la, (2-hydroxyethyl) di-isopropylmethylammonium bromide xanthene-9carboxylatel is a quaternary ammonium compound possessing anticholinergic properties, used for some years in the treatment of peptic ulcer and renal colic. This compound appears to undergo appreciable metabolism in man, even after intravenous administration (Beermann, Hellstrom & Rosen, 1972). Following oral administration of "4C-labelled propantheline bromide to normal men some 70% of the administered radioactivity was excreted in urine, but the majority of this was present as metabolites of the drug (Beermann et al., 1972; Vose, Prout, Haskins, Ford, Palmer &
Tidd, 1978). These metabolites included xanthanoic acid, hydroxyxanthanoic acid, hydroxypropantheline, and a number of conjugates. While the metabolism of this drug has been studied, little is known about its pharmacokinetics. This reflects the difficulty in quantifying propantheline bromide in biological fluids. A spectrophotometric method (Pfeffer, Schar, Bolton & Jacobsen, 1968) and a fluorimetric method (Westerlund & Karset, 1970), utilizing ion pair extraction techniques, have been reported. However, these did not have the necessary sensitivity to measure low concentrations of propantheline bromide. Recently a more sensitive and specific assay for
90
C.W. VOSE ETAL.
The present report .describes the application of this sensitive assay to a study of the -plasma concentrations and urinary -.excretion of propantheline bromide in normal} man following single intravenous and oral doses of the compound, and provides some pharmacokinetic data not previously available for this compound.
CH (CH3 )2
.1I
COCH2 CH2N-C4(CH3 )2
Br 0
a R=-CH3 b R=CD3
Methods
Figure 1 Chemical-structures of (a) propantheline bromide and (b) deuterium labelled propantheline
bromide.
propantheline bromide in. urine and plasma has been developed in these laboratories -(Ford, Guigson, -Haskins, Palmer, Prout & Vose,. 1977). This allows the compound.to be accurately.quantified in these biological fluids, with a quantitation. limit of about 5 ng ml-'. This assay uses the deuterium labelled compound (Figure lb) as te.i.trnal stadard, and multiple ion monitoring to --measure propantheline bromide in biological fluids by gas chromatography-mass spectrometry.
-
Propanthlfine bromide was obtained from Searle de Mexico, S.A. de C.V., Mexico City. The intravenous dosage was prepared by dissolving propantheline bromide (15-.mg) in sterile 0.9% saline (5 ml), and the oral -solution was prepared by dissolving the drug (15 mg) in distilled water (150 ml), immediately prior to dosage.
Clinical procedure The subjects weresix-..normal men aged 21-24-years who had given informed consent tQ participate in the study, and were judged healthy by a medical and
Table 1 P-Plasrs conce*etions (ng mf-1) of propantheline brQmide following a sinle intravenourdose
Time (min) 3 5
10 15
130 60 90
120 150 180 240
R{;
.JZ
1231 665 333 1 67 145 -38.0 26.0 0 0 0 0
786 457 *208 J28 067.2 .-36.6 27-2 24.2 31.7 :22.6 14#3
VP
*896 534 -249 192 102
6&8 33.2 28.3 24.2 18.9
15;8
Subject V)
1310 924 , 499 329 171 93.2 -Q0.0 37.7 44.5 29.1 : 27.2
JG
*494 285
440
97.0 *-45.0 20.0 -25.0 14.0 4.1 4.5 0
RH
Mean
.544 308 142 *72.5 40.0
876.8 528.8 261.8 164.3 95.0 45.8 31.2 19.9 19.3 14.2 10.6
20.0
16.0 15.0 1 tO 10.0 6,0
TabI2 Half-i and cWarancofintravenoupropanthelinebroaodde Su*ct
T.{ (min)
Tjb-(Mln)
RG
3.6 -3.6 1.2 3.0 -42
49.2 106.2 12.6
Jz
VP VD JG FRH Mean
'3.6
:3.2
qT-
c(hJ
1 9t8
2.16 3.69
54105.0 57:9
2.93
'
a'Distributiowtphase; b'Fet' eNrninetin phase; c 'SloW elimination pbase
Plasma cleauce 1 h-1)
Total
Renal
66.2 6&.3 53.4
13.6 15.7 10.0 6.7 12.0
28.1 137.7 121.2 79.2
*10.9 11.5
PROPANTHELINE BROMIDE PHARMACOKINETICS
biochemical pre-trial screen. The subjects fasted and abstained from all liquids for 10 h prior to dosage, except for the ingestion of 200 ml water 1 h before dosage. The subjects were forbidden alcohol from 24 h before dosing until sample collection was completed for each experiment, and all forms of medication were forbidden from 2 weeks before the study until its completion. A 1 week wash-out interval was allowed between each pha-se of the study. On the morning of dosing each volunteer received propantheline bromide (15 mg), intravenously, or as an oral solution in water (150 ml) in a balanced random crossover. The intravenous administration of the drug was carried out at a constant rate over 2.5 min. Urine samples were collected for 12 h before dosage and during 0-2, 2-4, 4-6, 6-8, 8-12, 12-24, 24-48, 48-72 and 72-96 h after dosage, into vessels containing 1 M perchioric acid (10 ml), and stored frozen at -200C. Blood samples (10 ml) were obtained from an antecubital vein immediately before dosage, and at 3*, 5* (* these samples were taken only after the intravenous dose), 10, 15, 30 and 60 min, and 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24,27, 30,48, 72 and 96 h after dosage. Each blood sample was immediately transferred to a heparinised tube, acidified, centrifuged, and the separated plasma was added to an equal volume of 0.1 M perchloric acid and frozen at - 200C within one hour of collection. Extraction and analysis of propantheline bromide in plasma and urine An aliquot of each urine sample (10 ml) and each acidified plasma sample (5 ml, equivalent to 2.5 ml of plasma) was extracted and analyzed by the method described previously (Ford et al, 1977). Table 3 Mean cumulative urinary excretion of propantheline bromide in 48 h following intravenous and oral administration of the drug Subject
RG Jz
VP VD JG
Rt Mean
% dose of propanthetne bromide excreted as intact drug Intravenoua
Oral
20.50 23.02 18.81 23.69 8.73 8.96 17.3
0.33 1.90
0.60 2.05
0.50
0.54 1.08
* Urine collections wer obtained only up to 12 h after dosage, this value not included in calcuating
mean value
91
Pharmacokinetic analysis of the plasma concentration and urinary excretion data was made using Metzler's NONLIN programme. Results In all six subjects propantheline bromide was rapidly cleared from plasma after intravenous administration (Table 1). The mean concentration decreased rapidly from 876.8 ng ml-l (range 494-1310 ng ml-') at 3 min after dosage, to 95 ngml-l (range 40.0-171.0ngml-') 30min after the i.v. dose. Thereafter the plasma levels of propantheline bromide decreased more slowly to 10.6 ng ml-' (range 0 to 27.2 ng ml-') at 4 h after administration. At all subsequent sampling times plasma concentrations of the drug were below the level of accurate quantitation (5 ng ml-'). In four of the subjects the plasma levels of propantheline bromide exhibited a biphasic decline, whereas in the other two subjects a third phase could be resolved. The half-lives of these phases are listed in Table 2 with other pharmacokinetic parameters. The initial (distribution) phase had a half-life of 3.2 min (range 1.2-4.2 min) and the second ('fast' elimination) phase had a half-life of 57.9 mm (range 12.6-106.2 min). The third ('slow' elimination) phase observed for subjects VP and VD had a half-life of 2.16 and 3.69 respectively. Following the oral dose of propantheline bromide plasma levels were very low, at or below the precision level of the assay (5 ng ml-') at all times after administration, and could not be accurately measured. The cumulative urinary excretion data listed in Table 3 showed that 17.3% (range 8.73-23.69%) of the intravenous propantheline bromide was excreted in urine. However, only 1.08% (range 0.33-2.05%) of the oral dose was eliminated by this route. The majority of the urinary excretion occurred in the first 8 h regardless of the route of administration. From the plasma concentrations and the urinary excretion data the plasma clearances of intravenous propantheline bromide were calculated (Tabe 2). There was a large inter-individual variation in the total plasma clearance, which ranged from 28.11 kh-I in 137.71 ' in subject 1G. In contms subject VD to there was a much smaller inter-individual variation in the plasma renal clearance from 6.7 to 15.7 1 h-l. During the study subjective observations of pharmacological effects of propantheline -bromide were reported by the subjects. Thus, following the oral dose they reported a deecree in salvary secretion, reflected by a dry mouth. This effect qieared between 30 and 6Gmi after dosage and lasted for a furthr I to 3 h. Following the intravenous doae this dry mouth sensation developed more rapidly, in some cases within a few minutes, and was of higher intensity and longer daration. In addition uriary hesitancy was
92
C.W. VOSE ETAL.
observed tbolowimg the i.v. dose, and was reflected by the absence of urine samples for the first 3 or 4 collection periods in some of the volunteers.
Discussion The rapid disappearance of intravenously administered propantheline bromide from plasma demonstrates a fast distribution and elimination of this drug in man. The half-lives of the phases associated with the decline in the plasma concentration of propantheline bromide are similar to those reported for a number of other quaternary ammonium compounds (Calvey, Williams, Muir & Barber, 1976; Scoular, Monks, Burgess & Turner, 1977). The very low plasma concentrations of propantheline bromide achieved after oral administration precluded their accurate measurement, and so no estimate of the rate of absorption could be obtained. This plasma level data, and the low urinary excretion of the orally administered drug indicated a low systemic availability, about 6.2% based on the mean cumulative urinary excretion data. This may account for the observed therapeutic ratio of the drug when given orally and parenterally (Moller & Rosen, 1968). Low plasma levels of orally administered propantheline bromide have been reported previously by Westerlund & Karset (1970), who found plasma levels of the drug were below 40 ng ml-" (the precision level of their assay) at all times after a 30 mg oral dose. The urinary excretiot of propantheline bromide observed in the present study following its intravenous and oral administration are similar to those reported by Beermann et al. (1972) in a study of a radiolabelled form of the compound. The mean plasma clearance data collected in the present study demonstrates a high total plasma clearance of propantheline bromide, 79.2 1 h-' (range 28.1-137.7 1 h-1). However, the renal clearance of the drug was low, 11.5 1 h-1 (range 6.7-15.7 1 h-1). Thus, urinary excretion is a minor route of elimination for propantheline bromide in man, the major routes of elimination being extra-renal. Since propantheline bromide is known to be appreciably metabolized after
intravenous administration (Beermann et al., 1972) this high extra-renal clearance probably reflects the importance of metabolism in the elimination of the drug. The inter-individual variation in the plasma renal clearance was low whereas the variation in total clearance was large. This suggests that the major source of inter-individual variation in the pharmacokinetics and pharmacology of propantheline bromide is the inter-individual difference in the extra-renal clearance of the drug. The apparently low systemic availability of orally administered drug observed in the present study has been reported previously (Beermann et al., 1972) from studies using carbon-14 labelled propantheline bromide. These workers suggested that this low availability reflected the enzymatic hydrolysis of the drug in the gastro-intestinal lumen and the poor absorption of quaternary ammonium compounds (Levine & Pelikan, 1964). However, the present study indicates that extra-renal routes, probably metabolism as discussed above, are the major pathways of elimination of propantheline bromide. Thus the low systemic availability of this compound may also result from a 'first pass' metabolism of the absorbed drug following oral administration. Although the present study indicates a low availability of oral propantheline bromide there is good evidence of its pharmacological activity in man (Moller & Rosen, 1968; Gibaldi & Grundhofer, 1975). These workers demonstrated a dose related suppression of salivary secretion with increasing oral doses of propantheline bromide. Since for most anticholinergics suppression of salivary secretion reflects the suppression of gastric secretion (Ivey, 1975) these studies provide evidence of the effectiveness of orally administered propantheline bromide. Further evidence of the pharmacological activity of this drug after oral administration was provided in the present study by the subjective observation of anticholinergic side effects in men having very low plasma levels of propantheline bromide. The pharmacokinetic data described in the present report may be of value in further studies on propantheline bromide and in studies of the relationship between blood levels and pharmacological activity.
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(Received December 21, 1977)
