Xenobiotica the fate of foreign compounds in biological systems
ISSN: 0049-8254 (Print) 1366-5928 (Online) Journal homepage: http://www.tandfonline.com/loi/ixen20
The Metabolic Fate of Prazosin J. A. Taylor, T. M. Twomey & M. Schach Von Wittenau To cite this article: J. A. Taylor, T. M. Twomey & M. Schach Von Wittenau (1977) The Metabolic Fate of Prazosin, Xenobiotica, 7:6, 357-364 To link to this article: http://dx.doi.org/10.3109/00498257709035794
Published online: 22 Sep 2008.
Submit your article to this journal
Article views: 41
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Citing articles: 7 View citing 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: 05 November 2015, At: 12:47
XENOBIOTICA,
1977, VOL. 7,
NO.
6, 357-364
The Metabolic Fate of Prazosin J. A. TAYLOR, T. M. TWOMEY and M. SCHACH VON WITTENAU Medical Research Laboratories, Pfizer Central Research, Groton, Connecticut 06340, U.S.A.
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
(Received 2 July 1976; accepted 6 December 1976) 1. [2-14C]Prazosin is rapidly distributed into tissues of the dog including heart, lung and vascular tissues. 2. Urinary excretion by rats and dogs is low, biliary secretion being the major route of elimination. 3 . Riotransformation of prazosin in the rat and dog occurs primarily by 6- or 7-0-dealkylation and subsequent glucuronide formation, and to a lesser extent via N-dealkylation. 4. Preliminary metabolic studies in man indicate a pattern of metabolites similar to that observed in dogs and rats.
Introduction Prazosin, 2-[4-(2-furo~l)-piperazin-l-yl]-4-amino-6,7-dimethoxyquinazoline hydrochloride is a structurally and mechanistically novel antihypertensive agent which lowers blood pressure primarily by direct vasodilation of arterioles (Hess, 1975). A detailed account of the pharmacological effects of prazosin has been presented by Constantine et al. (1973). The following studies were conducted to determine the absorption, distribution, metabolism and excretion of [2J4C]prazosin in rats and dogs. Preliminary information has also been obtained in man with unlabelled drug. Experimental [2-14C]Prazosin was prepared from K14CN0 by the sequence of reactions, shown in Fig. 1. The final product was obtained in Zoo/, yield with a specific activity of 4.47 pCi/mg as the hydrochloride salt (4.90 pCi/mg expressed as the free base). The radiochemical purity of labelled drug was > 9 9 % as shown by t.1.c. All animal studies were conducted with the salt. Doses are expressed as base equivalent.
+
K'CNO
0
Reflux
Fig. 1. Radiochemical synthesis of [2-14C]prazosin.
I
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
358
J . A. Taylor et al.
Radiochemical assay Urine and bile samples (0.2 ml aliquots) were dissolved in 15 ml of a liquid scintillation solution consisting of ethanol-toluene (30 : 70) with 5 g/1 Omnifluor (New England Nuclear). Radioactivity (I") was measured in a Nuclear Chicago Mark I liquid scintillation spectrometer and corrected for quenching and counting efficiency by internal standardization using [14C]toluene. Results were calculated in terms of [14C]prazosin equivalents. Fresh faecal samples were homogenized in a Waring Blender with the addition of water. T h e resultant slurry was lyophilized. Approximately 50 mg of dry lyophilate was combusted in an atmosphere of oxygen in a modified Schoniger flask or alternatively with an Oxymat Combustion apparatus (Intertechnique). Combustion products were trapped in 10 ml of ethanolaminoethyl cellosolve (1 : 2, v/v). Duplicate 1 ml aliquots of this solution were counted in 30 : 70 scintillator solution. Tissue distribution study [14]Prazosin was given intravenously in a single 0.40 mg/kg dose to a normal healthy male mongrel dog. After 30 min the dog was sacrificed by exsanguination and blood was collected. This animal was autopsied and selected tissue samples were removed for radioassay. Individual tissue samples were cut into small pieces and 25-100 mg of each tissue was transferred to a tared scintillation vial. Hyamine was added (1.0 ml) and samples in duplicate were digested at 70" for approximately 18 h. Samples were dissolved in 30 : 70 scintillator solution and radioactivity measured as described above.
Excretion studies Four male white rats (Charles River strain) weighing approx. 200 g were given an intravenous dose of 1*0mg/kg base equivalent of [14C]prazosin in aqueous solution. A similar dose was given orally to four additional male white rats. Animals were maintained in plastic metabolism cages and total urine and faecal collections were made from 0-24, 24-48 and 48-72 h after dose. Free access to feed and water was provided following drug administration. Two adult male beagle dogs weighing approx. 8.5 kg were given a 1.0 mg/kg oral dose of [14C]prazosin in aqueous solution. After a two week interval, the same two animals received a similar dose by intravenous administration. Urine and faeces were collected in both experiments from 0-24, 24-48 and 48-72 h after dose. To determine the biliary excretion of drug and/or metabolite, one adult male white rat (200 g) was anaesthetized with ether and a ventral midline incision was made. A polyethylene cannula was inserted into the common bile duct, fastened securely with silk suture and the free end was brought through the abdominal wall. The rat was then maintained in a restraining cage with free access to food and water. After 6 h an aqueous solution of [14C]prazosin was administered intraperitoneally at a dose of 1.0 mg/kg and bile was collected for 24 h. The drug was administered in this manner in three repetitive doses at
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
Praxosin Metabolism
359
24 h intervals to obtain sufficient quantities of 14C-labelled metabolites for identification studies. Biliary excretion of the drug as per cent of administered dose was determined. A chronic total biliary fistula was prepared in an adult beagle dog (8.0 kg) via aseptic cholecystectomy and cannulation of the common bile duct. A midline laparotomy under general anaesthetic was performed for isolation of the common duct and ligation and resection of the gall bladder. Silastic tubing (BectonDickinson Co.) inserted into the bile duct was connected at the opposite end to a Zeman cannulation device (Kanek Tool Corp.) which was positioned through the abdominal wall via a stab wound lateral to the primary incision. Post operative care was routine except that diet was supplemented with bile salts. Labelled prazosin was given orally at a dose of 1 mg/kg in capsule form. Urine and bile were then collected for 72 h.
Isolation and identification of metabolites Aliquots of rat and dog bile were applied without prior extraction to t.1.c. plates. Drug and metabolites were separated by development with one of three (75 : 20 : 5), (2) solvent systems : (1) ethyl acetate-methanol-diethylamine ethyl acetate-methanol(2 : l),(3) ethyl acetate-methanol-acetic acid (85 : 15 : 5). Most results were obtained with the latter system. Reference compounds run along with unknowns were detected under U.V.light by their absorption at 254 nm. Variation in R, values noted between runs was such that it was necessary to overlap streaks of standards added to bile and unknown bile samples with each run to verify the presence of metabolites. Zones containing 14Cwere visualized by autoradiography with Kodak Blue Brand X-ray film which permitted detection of 2 5000 d.p.m. in a single 10-15 cm streak. Drug-related polar materials that did not migrate in the t.1.c. solvent systems employed were eluted from silica gel with methanol, taken to dryness under nitrogen and redissolved in aqueous solution adjusted to p H 4.5. These polar compounds were subjected to enzymic hydrolysis for 16 h at 37" with Glusulase (P-glucuronidase + sulphatase, Endo Labs. Inc., Garden City, N.Y.). Polar materials were also separately subjected to treatment with aryl sulphatase. After enzymic treatment, solutions were extracted with ethyl acetate before t.1.c. or applied directly to t.1.c. plates and separated as described above. Metabolites separated by t.1.c. were eluted from silica gel with ethyl acetate and/or methanol. Appropriate aliquots of all labelled zones separated by t.1.c. were assayed for radioactivity both before and after Glusulase treatment. Relative metabolite concentrations were then determined as ratios of radioactivity in individual zones to total eluted radioactivity. Eluate samples were also concentrated to appropriate volumes and injected into a L K B 9000 combined g.1.c.-mass spectrometer interfaced with a PDP-8 computer for data acquisition. A 14C-radiomonitor was used to verify the presence of drugrelated peaks separated on a 1% OV-1 column. The column temperature was increased from 150" to 280" at a programmed rate of lO"/min. Mass spectra were obtained for all major peaks separated by g.1.c. Drug-related products which did not yield g.1.c. peaks were taken to dryness and identified from mass spectra obtained by a solid probe technique. Metabolite identification
r. A. Taylor et al.
3 60
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
was verified by comparison of R, values and g.1.c. retention times when authentic reference standards were available. The presence of prazosin in faecal homogenate, urine and bile was also determined by reverse isotope dilution studies.
Results Tissue distribution of radioactivity in the dog after an intravenous doseof [14C]prazosin Following an intravenous dose of [14C]prazosin, radioactivity was rapidly taken up into several tissues of the dog. Thirty minutes after drug administration, the highest levels of radioactivity were found in lung tissue, 1.23p.g prazosin equiv./g tissue; coronary arteries, 1.11; aorta, 0.68; paw arteries, 0.58 ; and heart, 0.54. Significantly lower radioactivity was noted in bronchial tissue, 0.22; plasma, 0.17; and skeletal muscle, 0.12, while very low levels were seen to cross the blood-brain barrier (brain stem, 0.05; brain, 0.03 pg prazosin equiv. /g tissue). Urinary and faecal excretion of 14C in rats and dogs after a single oral dose of [l4CJprnzosin The excretion pattern of radioactivity following the oral and intravenous administration of 1.0 mg/kg [14C]prazosin to rats is shown in Table 1. Total recoveries of 14C from combined excreta were similar after oral and intravenous doses. The majority of activity was recovered from faeces within 24 h. Table 1. Urinary and faecal excretion of I4C by rats after a single oral or intravenous dose of [I4C]prazosin Excretion Oral dose ____
Time (h)
0-24 24-48 48-72 Total in 0-72 h
(y, of dose) Intravenous dose Urine Faeces Total
Urine
Faeces
Total
7.6 +_ 2.5
64.9 f13.3
72.5 f13.5
i 1.5
0.7 2 0.2
14.5 f14.3
15.2 k14.3
+ 0.2
1.1 & 0.8
1.1 I03
80.5 6.2
* 3.7
-
8.3 f 2.5
88.8
11.9 0.6
-
69.3 i0.9 4.6
81.2 & 1.2
5.2
f 3.1
+ 3.1
0.6
*t0.6 0.1
f0.1
12.5
74.5
87.0
& 1.6
f 3.7
f 2.5
Values are means +_ S.D. for 4 rats in each group (oral or intravenous) given 1 mg/kg [14C]prazosin in aqueous solution.
The urinary and faecal excretion of radioactivity by dogs after oral and intravenous administration of [14C]prazosin is given in Table 2. As with rats, the major portion of activity was recovered from faeces within 24 h. T h e lower
Prazosin Metabolism
361
recovery of drug-related material in 0-24 h faeces after an oral dose compared to that following a similar intravenous dose, could be the result of incomplete combustion during radiochemical assay, incomplete collection or non-homogeneous blending of faecal homogenates. Table 2. Urinary and faecal excretion of I4C by dogs after a single oral or intravenous dose of [i4C]prazosin
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
Excretion
(yoof
dose)
Oral dose Time (h)
Intravenous dose
Urine
Faeces
Total
Urine
Faeces
Total
0-24
5.2 0.9
51.9 54.4
57.1 55.3
4.7 5.3
70.5 72.3
75.2 77.6
24-48
0.4 0.3
6.2 8.1
6.6 8.4
0.7 0.5
6.2 3.2
6.9 3.7
48-72
0.1 0.1
0.5 0.6
0.6 0.7
0.1 0.2
0.5 0.6
0.6 0.8
3.5
60.8
64.3
5.7
76.7
82.4
Total in 0-72 h
Values represent data for 2 dogs given 1 mg/kg ['*C]prazosin by oral and intravenous routes at 1 week interval. Total excretion in 72 h represents mean values for the 2 dogs.
Biliary secretion of 14Cin rats and dogs When [14C]prazosin was given intraperitoneally to a bile-cannulated rat, 40% of dose was excreted with bile within 24 h. This represents slightly more than half of the amount excreted with faeces by non-cannulated rats after a similar intravenous dose. After a single oral dose of [14C]prazosin was given to a bile fistula dog, 50% of dose was recovered from bile within 72 h. This represented more than 80% of dose excreted with faeces by non-cannulated dogs after an oral dose and approximately 75% of dose excreted with faeces after an intravenous dose.
Isolation and identijication of metabolites Several l4C-labelled metabolites of prazosin were excreted by rats and dogs in urine, and also in faeces subsequent to biliary secretion (Table 3). Prazosin, 2-( 1-piper azinyl)-4-amino- 6 , 7-dime t hoxy quinazoline and 2,4-diamino-6,7dimethoxyquinozaline, present in minor quantities were identified by t.1.c. and mass spectral comparison with authentic reference standards. Following Glusulase treatment and t.1.c. separation, a major unknown drugrelated component was isolated. A parent molecular ion of 368 mass units was indicated by mass spectra obtained by a solid probe technique at 70 eV while at 12.5 eV the abundance ratio of masses 3691368 increased significantly. X.B.
2c
0.16 7-0-Demethyl Prazosin
0.00 2-(l-Piperazinyl)4-amino-6,7dimethoxyquinazoline
0.24 2,4-Diamino-6,7dimethoxyquinazoline
0.34
0.15
0.00
0.09
0.47
0.43
0.24
0.41
no
n
CH30
CHBO
'
3
0
I a
NH2
NHZ
N
n
Free Conjugated
Free Conjugated
Conjugated
Conjugated Free
1 ND
1 ND
ISSN: 0049-8254 (Print) 1366-5928 (Online) Journal homepage: http://www.tandfonline.com/loi/ixen20
The Metabolic Fate of Prazosin J. A. Taylor, T. M. Twomey & M. Schach Von Wittenau To cite this article: J. A. Taylor, T. M. Twomey & M. Schach Von Wittenau (1977) The Metabolic Fate of Prazosin, Xenobiotica, 7:6, 357-364 To link to this article: http://dx.doi.org/10.3109/00498257709035794
Published online: 22 Sep 2008.
Submit your article to this journal
Article views: 41
View related articles
Citing articles: 7 View citing 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: 05 November 2015, At: 12:47
XENOBIOTICA,
1977, VOL. 7,
NO.
6, 357-364
The Metabolic Fate of Prazosin J. A. TAYLOR, T. M. TWOMEY and M. SCHACH VON WITTENAU Medical Research Laboratories, Pfizer Central Research, Groton, Connecticut 06340, U.S.A.
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
(Received 2 July 1976; accepted 6 December 1976) 1. [2-14C]Prazosin is rapidly distributed into tissues of the dog including heart, lung and vascular tissues. 2. Urinary excretion by rats and dogs is low, biliary secretion being the major route of elimination. 3 . Riotransformation of prazosin in the rat and dog occurs primarily by 6- or 7-0-dealkylation and subsequent glucuronide formation, and to a lesser extent via N-dealkylation. 4. Preliminary metabolic studies in man indicate a pattern of metabolites similar to that observed in dogs and rats.
Introduction Prazosin, 2-[4-(2-furo~l)-piperazin-l-yl]-4-amino-6,7-dimethoxyquinazoline hydrochloride is a structurally and mechanistically novel antihypertensive agent which lowers blood pressure primarily by direct vasodilation of arterioles (Hess, 1975). A detailed account of the pharmacological effects of prazosin has been presented by Constantine et al. (1973). The following studies were conducted to determine the absorption, distribution, metabolism and excretion of [2J4C]prazosin in rats and dogs. Preliminary information has also been obtained in man with unlabelled drug. Experimental [2-14C]Prazosin was prepared from K14CN0 by the sequence of reactions, shown in Fig. 1. The final product was obtained in Zoo/, yield with a specific activity of 4.47 pCi/mg as the hydrochloride salt (4.90 pCi/mg expressed as the free base). The radiochemical purity of labelled drug was > 9 9 % as shown by t.1.c. All animal studies were conducted with the salt. Doses are expressed as base equivalent.
+
K'CNO
0
Reflux
Fig. 1. Radiochemical synthesis of [2-14C]prazosin.
I
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
358
J . A. Taylor et al.
Radiochemical assay Urine and bile samples (0.2 ml aliquots) were dissolved in 15 ml of a liquid scintillation solution consisting of ethanol-toluene (30 : 70) with 5 g/1 Omnifluor (New England Nuclear). Radioactivity (I") was measured in a Nuclear Chicago Mark I liquid scintillation spectrometer and corrected for quenching and counting efficiency by internal standardization using [14C]toluene. Results were calculated in terms of [14C]prazosin equivalents. Fresh faecal samples were homogenized in a Waring Blender with the addition of water. T h e resultant slurry was lyophilized. Approximately 50 mg of dry lyophilate was combusted in an atmosphere of oxygen in a modified Schoniger flask or alternatively with an Oxymat Combustion apparatus (Intertechnique). Combustion products were trapped in 10 ml of ethanolaminoethyl cellosolve (1 : 2, v/v). Duplicate 1 ml aliquots of this solution were counted in 30 : 70 scintillator solution. Tissue distribution study [14]Prazosin was given intravenously in a single 0.40 mg/kg dose to a normal healthy male mongrel dog. After 30 min the dog was sacrificed by exsanguination and blood was collected. This animal was autopsied and selected tissue samples were removed for radioassay. Individual tissue samples were cut into small pieces and 25-100 mg of each tissue was transferred to a tared scintillation vial. Hyamine was added (1.0 ml) and samples in duplicate were digested at 70" for approximately 18 h. Samples were dissolved in 30 : 70 scintillator solution and radioactivity measured as described above.
Excretion studies Four male white rats (Charles River strain) weighing approx. 200 g were given an intravenous dose of 1*0mg/kg base equivalent of [14C]prazosin in aqueous solution. A similar dose was given orally to four additional male white rats. Animals were maintained in plastic metabolism cages and total urine and faecal collections were made from 0-24, 24-48 and 48-72 h after dose. Free access to feed and water was provided following drug administration. Two adult male beagle dogs weighing approx. 8.5 kg were given a 1.0 mg/kg oral dose of [14C]prazosin in aqueous solution. After a two week interval, the same two animals received a similar dose by intravenous administration. Urine and faeces were collected in both experiments from 0-24, 24-48 and 48-72 h after dose. To determine the biliary excretion of drug and/or metabolite, one adult male white rat (200 g) was anaesthetized with ether and a ventral midline incision was made. A polyethylene cannula was inserted into the common bile duct, fastened securely with silk suture and the free end was brought through the abdominal wall. The rat was then maintained in a restraining cage with free access to food and water. After 6 h an aqueous solution of [14C]prazosin was administered intraperitoneally at a dose of 1.0 mg/kg and bile was collected for 24 h. The drug was administered in this manner in three repetitive doses at
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
Praxosin Metabolism
359
24 h intervals to obtain sufficient quantities of 14C-labelled metabolites for identification studies. Biliary excretion of the drug as per cent of administered dose was determined. A chronic total biliary fistula was prepared in an adult beagle dog (8.0 kg) via aseptic cholecystectomy and cannulation of the common bile duct. A midline laparotomy under general anaesthetic was performed for isolation of the common duct and ligation and resection of the gall bladder. Silastic tubing (BectonDickinson Co.) inserted into the bile duct was connected at the opposite end to a Zeman cannulation device (Kanek Tool Corp.) which was positioned through the abdominal wall via a stab wound lateral to the primary incision. Post operative care was routine except that diet was supplemented with bile salts. Labelled prazosin was given orally at a dose of 1 mg/kg in capsule form. Urine and bile were then collected for 72 h.
Isolation and identification of metabolites Aliquots of rat and dog bile were applied without prior extraction to t.1.c. plates. Drug and metabolites were separated by development with one of three (75 : 20 : 5), (2) solvent systems : (1) ethyl acetate-methanol-diethylamine ethyl acetate-methanol(2 : l),(3) ethyl acetate-methanol-acetic acid (85 : 15 : 5). Most results were obtained with the latter system. Reference compounds run along with unknowns were detected under U.V.light by their absorption at 254 nm. Variation in R, values noted between runs was such that it was necessary to overlap streaks of standards added to bile and unknown bile samples with each run to verify the presence of metabolites. Zones containing 14Cwere visualized by autoradiography with Kodak Blue Brand X-ray film which permitted detection of 2 5000 d.p.m. in a single 10-15 cm streak. Drug-related polar materials that did not migrate in the t.1.c. solvent systems employed were eluted from silica gel with methanol, taken to dryness under nitrogen and redissolved in aqueous solution adjusted to p H 4.5. These polar compounds were subjected to enzymic hydrolysis for 16 h at 37" with Glusulase (P-glucuronidase + sulphatase, Endo Labs. Inc., Garden City, N.Y.). Polar materials were also separately subjected to treatment with aryl sulphatase. After enzymic treatment, solutions were extracted with ethyl acetate before t.1.c. or applied directly to t.1.c. plates and separated as described above. Metabolites separated by t.1.c. were eluted from silica gel with ethyl acetate and/or methanol. Appropriate aliquots of all labelled zones separated by t.1.c. were assayed for radioactivity both before and after Glusulase treatment. Relative metabolite concentrations were then determined as ratios of radioactivity in individual zones to total eluted radioactivity. Eluate samples were also concentrated to appropriate volumes and injected into a L K B 9000 combined g.1.c.-mass spectrometer interfaced with a PDP-8 computer for data acquisition. A 14C-radiomonitor was used to verify the presence of drugrelated peaks separated on a 1% OV-1 column. The column temperature was increased from 150" to 280" at a programmed rate of lO"/min. Mass spectra were obtained for all major peaks separated by g.1.c. Drug-related products which did not yield g.1.c. peaks were taken to dryness and identified from mass spectra obtained by a solid probe technique. Metabolite identification
r. A. Taylor et al.
3 60
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
was verified by comparison of R, values and g.1.c. retention times when authentic reference standards were available. The presence of prazosin in faecal homogenate, urine and bile was also determined by reverse isotope dilution studies.
Results Tissue distribution of radioactivity in the dog after an intravenous doseof [14C]prazosin Following an intravenous dose of [14C]prazosin, radioactivity was rapidly taken up into several tissues of the dog. Thirty minutes after drug administration, the highest levels of radioactivity were found in lung tissue, 1.23p.g prazosin equiv./g tissue; coronary arteries, 1.11; aorta, 0.68; paw arteries, 0.58 ; and heart, 0.54. Significantly lower radioactivity was noted in bronchial tissue, 0.22; plasma, 0.17; and skeletal muscle, 0.12, while very low levels were seen to cross the blood-brain barrier (brain stem, 0.05; brain, 0.03 pg prazosin equiv. /g tissue). Urinary and faecal excretion of 14C in rats and dogs after a single oral dose of [l4CJprnzosin The excretion pattern of radioactivity following the oral and intravenous administration of 1.0 mg/kg [14C]prazosin to rats is shown in Table 1. Total recoveries of 14C from combined excreta were similar after oral and intravenous doses. The majority of activity was recovered from faeces within 24 h. Table 1. Urinary and faecal excretion of I4C by rats after a single oral or intravenous dose of [I4C]prazosin Excretion Oral dose ____
Time (h)
0-24 24-48 48-72 Total in 0-72 h
(y, of dose) Intravenous dose Urine Faeces Total
Urine
Faeces
Total
7.6 +_ 2.5
64.9 f13.3
72.5 f13.5
i 1.5
0.7 2 0.2
14.5 f14.3
15.2 k14.3
+ 0.2
1.1 & 0.8
1.1 I03
80.5 6.2
* 3.7
-
8.3 f 2.5
88.8
11.9 0.6
-
69.3 i0.9 4.6
81.2 & 1.2
5.2
f 3.1
+ 3.1
0.6
*t0.6 0.1
f0.1
12.5
74.5
87.0
& 1.6
f 3.7
f 2.5
Values are means +_ S.D. for 4 rats in each group (oral or intravenous) given 1 mg/kg [14C]prazosin in aqueous solution.
The urinary and faecal excretion of radioactivity by dogs after oral and intravenous administration of [14C]prazosin is given in Table 2. As with rats, the major portion of activity was recovered from faeces within 24 h. T h e lower
Prazosin Metabolism
361
recovery of drug-related material in 0-24 h faeces after an oral dose compared to that following a similar intravenous dose, could be the result of incomplete combustion during radiochemical assay, incomplete collection or non-homogeneous blending of faecal homogenates. Table 2. Urinary and faecal excretion of I4C by dogs after a single oral or intravenous dose of [i4C]prazosin
Downloaded by [University of California Santa Barbara] at 12:47 05 November 2015
Excretion
(yoof
dose)
Oral dose Time (h)
Intravenous dose
Urine
Faeces
Total
Urine
Faeces
Total
0-24
5.2 0.9
51.9 54.4
57.1 55.3
4.7 5.3
70.5 72.3
75.2 77.6
24-48
0.4 0.3
6.2 8.1
6.6 8.4
0.7 0.5
6.2 3.2
6.9 3.7
48-72
0.1 0.1
0.5 0.6
0.6 0.7
0.1 0.2
0.5 0.6
0.6 0.8
3.5
60.8
64.3
5.7
76.7
82.4
Total in 0-72 h
Values represent data for 2 dogs given 1 mg/kg ['*C]prazosin by oral and intravenous routes at 1 week interval. Total excretion in 72 h represents mean values for the 2 dogs.
Biliary secretion of 14Cin rats and dogs When [14C]prazosin was given intraperitoneally to a bile-cannulated rat, 40% of dose was excreted with bile within 24 h. This represents slightly more than half of the amount excreted with faeces by non-cannulated rats after a similar intravenous dose. After a single oral dose of [14C]prazosin was given to a bile fistula dog, 50% of dose was recovered from bile within 72 h. This represented more than 80% of dose excreted with faeces by non-cannulated dogs after an oral dose and approximately 75% of dose excreted with faeces after an intravenous dose.
Isolation and identijication of metabolites Several l4C-labelled metabolites of prazosin were excreted by rats and dogs in urine, and also in faeces subsequent to biliary secretion (Table 3). Prazosin, 2-( 1-piper azinyl)-4-amino- 6 , 7-dime t hoxy quinazoline and 2,4-diamino-6,7dimethoxyquinozaline, present in minor quantities were identified by t.1.c. and mass spectral comparison with authentic reference standards. Following Glusulase treatment and t.1.c. separation, a major unknown drugrelated component was isolated. A parent molecular ion of 368 mass units was indicated by mass spectra obtained by a solid probe technique at 70 eV while at 12.5 eV the abundance ratio of masses 3691368 increased significantly. X.B.
2c
0.16 7-0-Demethyl Prazosin
0.00 2-(l-Piperazinyl)4-amino-6,7dimethoxyquinazoline
0.24 2,4-Diamino-6,7dimethoxyquinazoline
0.34
0.15
0.00
0.09
0.47
0.43
0.24
0.41
no
n
CH30
CHBO
'
3
0
I a
NH2
NHZ
N
n
Free Conjugated
Free Conjugated
Conjugated
Conjugated Free
1 ND
1 ND
