120
Br. J. clin. Pharmac. (1979), 7
LETTERS TO THE EDITORS
Table 1 Pharmacokinetic parameters (mean + s.d.; n=4) of desmethyidiazepam in young and older male subjects
Young, Elderly Parameter (29-34 years) (65-85 years) P value T7 (h) Cl (ml/min) Vd8 (I/kg)
151 +60 51 +6.2 11.3 + 3.1 4.3 ± 1.5 0.64+ 0.17 0.85 ±0.14
0.008 0.003 0.07
References BOSTON
COLLABORATIVE
SURVEILLANCE
DRUG
PROGRAM (1973). Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N. Engl. J. Med., 288, 277-280. GIBALDI, M., NAGASHIMA, R. & LEVY, G. (1969). Relationship between drug concentration in plasma or serum and amount of drug in the body. J. pharm. Sci., 58, 193-197. KLOTZ, U., AVANT, G.R., HOYUMPA, A., SCHENKER, S. &
has been demonstrated to be cleared age-dependently (Shader, Greenblatt, Harmatz, Franke & KochWeser, 1977; Roberts, Wilkinson, Branch & Schenker, 1978). These studies with the benzodiazepines, which possess close chemical and biological activities, clearly demonstrate that there does not appear to be any consistent pattern of changes in the pharmacokinetics of drugs with age. Such inconsistency appears to be reflective of the complex situation of drug disposition and ageing in general and it requires the individual examination of each drug. It seems, that the conjugation of drugs might be less effected by the ageing process than hydroxylation. With respect to the lowered Cl of DD in the elderly, this fact will lead in those patients to a more pronounced accumulation of DD following multiple dosing with D or DD, which could account, at least partially, for the increased incidence of side effects observed in aged individuals treated with diazepam.
This study was supported by the Robert Bosch Foundation, Stuttgart, W. Germany. U. KLOTZ & P. MULLER-SEYDLITZ Dr. Margarete Fischer-Bosch-Institut fur Klinische Pharmakologie, Auerbachstr. 112, D-7000 Stuttgart 50, Germany Received October 4, 1978
WILKINSON, G.R. (1975). Effects of age and liver disease on the disposition and elimination of diazepam in adult man. J. clin. Invest., 55, 347-359. KLOTZ, U., ANTONIN, K.H. & BIECK, P.R. (1976). Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur. J. clin. Pharmac., 10, 121-126. KRAUS, J.W., DESMOND, P.V., MARSHALL, J.P., JOHNSON, R.F., SCHENKER, S. & WILKINSON, G.R.
(1978). The effects of aging and liver disease on the disposition of lorazepam in man. Clin. Pharmac. Ther., 24,411-419. RANDALL, L.O., SCHECKEL, C.L. & BANZINGER, R.F.
(1965). Pharmacology of the metabolites of chlordiazepoxide and diazepam. Curr. Ther. Res., 7, 590-606. ROBERTS, R.K., WILKINSON, G.R., BRANCH, R.A. &
SCHENKER, S. (1978). The effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide. Gastroenterology, 75, 479-485. SCHWARTZ, M.A., KOECHLIN, B.A., POSTMA, E., PALMER, S. & KROL, G. (1965). Metabolism of
diazepam in rat, dog, and man. J. Pharmac. exp. Ther., 149,423-435. SHADER, R.I., GREENBLATT, D.J., HARMATZ, J.S., FRANKE, K. & KOCH-WESER, j. (1977). Absorption and disposition of chlordiazepoxide in young and elderly male volunteers. J. clin. Pharmac., 17, 709-718. SHULL, H.J., WILKINSON, G.R., JOHNSON, R.F. & SCHENKER, S. (1976). Normal elimination of oxazepam
in acute viral hepatitis and cirrhosis. Ann. intern. Med., 84,420-425. WESTLAKE, WJ. (1970). Time integral of drug concentration in the central (plasma) compartment. J. pharm. Sci., 59, 722-723.
THE BIOTRANSFORMATION OF CICLAZINDOL IN MAN
Ciclazindol, Wy 23409 (Figure 1) is currently under investigation in the clinic as a potential antidepressant. The compound is derived from a novel tetrahydropyrimidoindole nucleus and the metabolism of such structures has not previously been reported. This communication describes studies on the biotransformation of ciclazindol in human volunteers.
The volunteers had received t2-14C] ciclazindol as part of a clinical pharmacokinetic study, the results of which have already been published (Swaisland, Franklin, Southgate & Coleman, 1977). Metabolites were extracted from the first-day urines using Amberlite XAD-2 resin. Chromatography was carried out using silica gel thin layers (Kontes
Br. J. clin. Pharmac. (I 9 7 9), 7
LETTERS TO THE EDITORS
121
Im
Cl ~ /S - OH
Ciclazindol 'Metabolite
N
m'
II
\~N I
Wy 23973 Metablite fb
v
N'OH OO H
S \/
0S
N(CH2)2COOH
N\ H
~~Metabolite Ba
(CH93NH2
'I?
Cl -
OH o
Wy 24773 Metabolite IV
(CH2)2COOH Figure 1 Metabolism of ciclazindol in man. *The structure shown for metabolite Ila is that of N-(3-m-
chlorophenyl-3-hydroxy-3H-indol-2-yl)- 3-aminopropionic acid.
®
Origin
®
© Solvent front
Figure 2 Thin layer chromatographic separation of urinary metabolites of ciclazindol. XAD-2 extracts of urine were chromatographed on silica gel thin layers developed in chloroform-acetone-acetic acidwater (60:20:20:5). Roman numerals indicate the system of nomenclature used in the text. A - position of Wy 23973; B - position of ciclazindol; C-position of Wy 24773.
action of diazomethane on Wy 24773 and the product of reaction ofmetabolite IV with diazomethane were indistinguishable in CAAW (RF 0.73), TEA (RF 0.47), toluene-ethanol-acetic acid (80:20:5) (RF 0.49) and chloroform-acetone-NH40H (sp. gr. 0.880)
(60:20:1)(RFO.43).
Quantum) developed mainly in chloroform-acetone -acetic acid-water (60:20:20:5, CAAW) or in toluene-ethanol-NH40H (sp. gr. 0.880) (80:20:1, TEA). The peaks of radioactivity resulting from the separation of the metabolites in CAAW were numbered as shown in Figure 2. The position of unchanged ciclazindol and Wy 23973 (see Figure 1), a compound produced by the action of mild alkali on ciclazindol, are also shown. Table 1 shows the RF values of the metabolites and some synthetic derivatives of ciclazindol in CAAW and TEA. Extraction of the urine with toluene under basic conditions removed a substance which was chromatographically indistinguishable from ciclazindol in both CAAW and TEA. Furthermore, the ultraviolet spectrum of this material was very similar to that of authentic ciclazindol (Figure 3a). Under acidic conditions toluene extracted a compound with the chromatographic properties of metabolite IV. This indication that an acidic metabolite was produced prompted comparative studies with Wy 24773 (see Figure 1), a carboxylic acid that could arise by oxidative deamination of Wy 23973. This acid was found to have similar chromatographic characteristics to metabolite IV both in CAAW and in TEA. Furthermore, the methyl ester produced by the
Metabolite II was chromatographically similar to Wy 23973 in CAAW, but when this band was eluted and chromatographed in TEA, two components were separated. These were designated Ila and Ilb. Metabolite Ilb had a similar RF to Wy 23973 in TEA. Furthermore, the ultraviolet spectrum of metabolite llb was similar to that of authentic Wy 23973 (Figure 3b). Table 1 RF values for metabolites and derivatives of ciclazindol in CAAW and TEA
RF CAA W Metabolite 11
Ill lV V
Ciclazindol Wy 23973 Wy 24773
0.03 0.66 0.78 0.85 0.95 0.78 0.66 0.85
values
TEA
(a) 0.08 (b) 0.29 0.68 0.08 +
0.68 0.29 0.08
+ The thin layer chromatography of these fractions was not investigated in this solvent system.
122
LETTERS TO THE EDITORS
a
Br. J. clin. Pharmac. (I 9 79), 7
b
c
5)
(i) .0
.0U)
A
2 240 2 3 240 280 340 .
200
..
I
.
220
.
I .
..
260 300 340
0
200
.
(ii)
2
. . 3 3.4
240
300 340
Wavelength (nm) Figure 3 (a) Ultraviolet spectra of (i) ciclazindol from human urine and (ii) authentic ciclazindol; (b) Ultraviolet spectra of (i) metabolite lIb from human urine and (ii) authentic Wy 23973; (c) Ultraviolet spectra of (i) metabolite Ila from human urine and (ii) N-(3-m-chlorophenyl-3-hydroxy-3H-indol-2-yl)-3-aminopropionic acid.
Figure 4 Structure of Wy 24192, the alcohol related to N-(3-m-chlorophenyl-3-hydroxy-3H-indol2-yl)-3-aminopropionic acid (metabolite Ila).
Metabolite Ila had a relatively distinctive u.v. spec(Figure 3c) which was similar to that of Wy 24192, an alcohol that could have arisen from ciclazindol by cleavage of the tetrahydropyrimidine ring between C4 and the indole nitrogen (Figure 4). However, it was clear from the t.l.c. behaviour that metabolite Ila was not Wy 24192, the low mobility of the metabolite in TIRA suggesting that it was acidic. The corresponding carboxylic acid derivative of Wy 24192 was synthesized and was found to be chromatographically indistinguishable from metabolite Ila both in CAAW and in TEA. Moreover, the methyl ester of the synthetic material produced by reaction with methanol in the presence of BF3 and the product of reaction of metabolite Ila with the same reagent were chromatographically identical in CAAW (RF trum
0.55), propan-2-ol-NH4OH (sp. gr. 0.880) (8:2) (RF 0.41), toluene-ethylformate-formic acid (5:4:1) (RF 0.12) and ethanol-methanol-diethylamine (65:10:5) (RF 0.57). The ultraviolet spectrum of metabolite IIa was also very similar to that of the authentic material (Figure 3c). Attempts were made to elucidate the nature of 'metabolite 1', material remaining on the origin, with various hydrolytic treatments. Incubation with 2M HCI resulted in a decrease of this material and an increase in ciclazindol, suggesting the presence of an acid-labile conjugate of the drug. The nature of this conjugate has not been further investigated. An increase in the proportion metabolito hIa apparently at the expense of ciclazindol in those incubations where alkaline buffers were used lends support to the assumption that metabolite Ila was Wy 23973, since ciclazindol is known to degrade to this compound under alkaline conditions. All of the metabolites that have been identified have been subjected to pharmacological and toxicological tests and all were less active than the parent compound. In conclusion, therefore, it appears that all the major urinary metabolites of ciclazindol arise from biotransformations of the tetrahydropyrimidine ring (Figure 1). This observation suggests that the metabolism of ciclazindol is similar to the structurally related mazindol, where metabolism in the rat was apparently exclusive to the imidazole ring (Dugger, Coombs, Schwartz, Migdalof & Orwig, 1976). A.J. SWAISLAND, R.A. FRANKLIN & A.C. WHITE Wyeth Laboratories, Taplow, Maidenhead, Berks. Received September 19, 1978
Br. J. clin. Pharmac. (1979), 7
References DUGGER, H.A., COOMBS, R.A., SCHWARTZ, H.J.,
MIGDALOF, B.H. & ORWIG, B.A. (1976). Biotransformation of Mazindol: I. Isolation and identification of some metabolites from rat urine. Drug Metab. Dispos., 4, 262-268.
LETTERS TO THE EDITORS
123
SWAISLAND, A.J., FRANKLIN, R.A., SOUTHGATE, P.J. & COLEMAN, A.J. (1977). The pharmacokinetics of ciclazindol (Wy 23409) in human volunteers. Br. J. cin. Pharmac., 4,61-65.
THE ROLE OF THE CLINICAL PHARMACOLOGIST IN DISTRICT GENERAL HOSPITALS
The criticism made by Fullerton & Noyce (1978) of your excellent statement (British Journal of Clinical Pharmacology, 1978) on this subject highlights two major issues: first, it rehearses most of the prejudices and misconceptions surrounding clinical pharmacology; and secondly, it shows with abundant clarity the direction from which the discipline can expect least support. The basis of Fullerton & Noyce's (1978) attack comes from their assertion that clinical pharmacology ', . . is a research-based discipline rather than practisebased'. They obviously do not know that undergraduate medical students are expected to pass examinations in this subject before they can practise medicine; that it is a recognized specialty within the National Health Service; that it has its own Specialty Advisory Committee within the Joint Committee on Higher Medical Training; and that many consultants, senior registrars and registrars are in post throughout the country. Your correspondents are obviously unaware that there are patients whose clinical problems are pharmacological in nature, and who benefit from the services of a specialist clinical pharmacologist. He parallels, precisely, the physician with an organ-based specialty such as cardiology, nephrology or gastroenterology (Rawlins, 1978). The suggestion that most of the functions of a District General Hospital clinical pharmacologist can be undertaken by pharmacists is laughable. The training of a pharmacist includes little physiology, pathology or clinical medicine, and it is naive to believe that experience in hospital pharmacies provides anything more than familiarity with medical terminology. Without the clinical training which a clinical pharmacologist obtains as an undergraduate (3 years), pre-registration house officer (1 year), during general professional training (3 years), and higher medical training (4 years), the successful application of modern pharmacology to the treatment of disease is impossible. The notion that clinical pharmacology should be
subjected to 'careful appraisal' is one which several of us have considered. Although it would be simple to analyse a clinical pharmacologist's working pattern, it would be much more difficult to assess 'benefit' (either positive or negative). Really useful information-such as his influence on the incidence of adverse drug reactions in his hospital and his community-would be so expensive to gather as to negate the exercise completely. Perhaps this is why Drug Information Services, of which Fullerton & Noyce (1978) speak so highly, have not been subjected to detailed cost-benefit analysis. Finally, Fullerton & Noyce (1978) are possibly unaware that the concept of DGH clinical pharmacologists originated-from the Royal College of Physicians (1974). Their suggestion that clinical pharmacologists have supported the scheme merely to expand their discipline is as insulting as it is inaccurate. M.D. RAWLINS Department of Pharmacological Sciences, Wolfson Unit of Clinical Pharmacology, University of Newcastle upon Tyne, Newcastle upon Tyne Received September 19, 1978
References BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(1978). The role of the clinical pharmacologist in district general hospitals. Br. J. clin. Pharmac., 5, 3-5. FULLERTON, S.E. & NOYCE, P.R. (1978). The role of the clinical pharmacologist in district general hospitals. Br. J. clin. Pharmac., 6, 180-181. RAWLINS, M.D. (1978). Clinical Pharmacology in the National Health Service. J. Roy. Soc. Med., 71, 556-557. ROYAL COLLEGE OF PHYSICIANS (1974). Report of the Committee on Clinical Pharmacology. London: Royal College of Physicians.
Br. J. clin. Pharmac. (1979), 7
LETTERS TO THE EDITORS
Table 1 Pharmacokinetic parameters (mean + s.d.; n=4) of desmethyidiazepam in young and older male subjects
Young, Elderly Parameter (29-34 years) (65-85 years) P value T7 (h) Cl (ml/min) Vd8 (I/kg)
151 +60 51 +6.2 11.3 + 3.1 4.3 ± 1.5 0.64+ 0.17 0.85 ±0.14
0.008 0.003 0.07
References BOSTON
COLLABORATIVE
SURVEILLANCE
DRUG
PROGRAM (1973). Clinical depression of the central nervous system due to diazepam and chlordiazepoxide in relation to cigarette smoking and age. N. Engl. J. Med., 288, 277-280. GIBALDI, M., NAGASHIMA, R. & LEVY, G. (1969). Relationship between drug concentration in plasma or serum and amount of drug in the body. J. pharm. Sci., 58, 193-197. KLOTZ, U., AVANT, G.R., HOYUMPA, A., SCHENKER, S. &
has been demonstrated to be cleared age-dependently (Shader, Greenblatt, Harmatz, Franke & KochWeser, 1977; Roberts, Wilkinson, Branch & Schenker, 1978). These studies with the benzodiazepines, which possess close chemical and biological activities, clearly demonstrate that there does not appear to be any consistent pattern of changes in the pharmacokinetics of drugs with age. Such inconsistency appears to be reflective of the complex situation of drug disposition and ageing in general and it requires the individual examination of each drug. It seems, that the conjugation of drugs might be less effected by the ageing process than hydroxylation. With respect to the lowered Cl of DD in the elderly, this fact will lead in those patients to a more pronounced accumulation of DD following multiple dosing with D or DD, which could account, at least partially, for the increased incidence of side effects observed in aged individuals treated with diazepam.
This study was supported by the Robert Bosch Foundation, Stuttgart, W. Germany. U. KLOTZ & P. MULLER-SEYDLITZ Dr. Margarete Fischer-Bosch-Institut fur Klinische Pharmakologie, Auerbachstr. 112, D-7000 Stuttgart 50, Germany Received October 4, 1978
WILKINSON, G.R. (1975). Effects of age and liver disease on the disposition and elimination of diazepam in adult man. J. clin. Invest., 55, 347-359. KLOTZ, U., ANTONIN, K.H. & BIECK, P.R. (1976). Comparison of the pharmacokinetics of diazepam after single and subchronic doses. Eur. J. clin. Pharmac., 10, 121-126. KRAUS, J.W., DESMOND, P.V., MARSHALL, J.P., JOHNSON, R.F., SCHENKER, S. & WILKINSON, G.R.
(1978). The effects of aging and liver disease on the disposition of lorazepam in man. Clin. Pharmac. Ther., 24,411-419. RANDALL, L.O., SCHECKEL, C.L. & BANZINGER, R.F.
(1965). Pharmacology of the metabolites of chlordiazepoxide and diazepam. Curr. Ther. Res., 7, 590-606. ROBERTS, R.K., WILKINSON, G.R., BRANCH, R.A. &
SCHENKER, S. (1978). The effect of age and parenchymal liver disease on the disposition and elimination of chlordiazepoxide. Gastroenterology, 75, 479-485. SCHWARTZ, M.A., KOECHLIN, B.A., POSTMA, E., PALMER, S. & KROL, G. (1965). Metabolism of
diazepam in rat, dog, and man. J. Pharmac. exp. Ther., 149,423-435. SHADER, R.I., GREENBLATT, D.J., HARMATZ, J.S., FRANKE, K. & KOCH-WESER, j. (1977). Absorption and disposition of chlordiazepoxide in young and elderly male volunteers. J. clin. Pharmac., 17, 709-718. SHULL, H.J., WILKINSON, G.R., JOHNSON, R.F. & SCHENKER, S. (1976). Normal elimination of oxazepam
in acute viral hepatitis and cirrhosis. Ann. intern. Med., 84,420-425. WESTLAKE, WJ. (1970). Time integral of drug concentration in the central (plasma) compartment. J. pharm. Sci., 59, 722-723.
THE BIOTRANSFORMATION OF CICLAZINDOL IN MAN
Ciclazindol, Wy 23409 (Figure 1) is currently under investigation in the clinic as a potential antidepressant. The compound is derived from a novel tetrahydropyrimidoindole nucleus and the metabolism of such structures has not previously been reported. This communication describes studies on the biotransformation of ciclazindol in human volunteers.
The volunteers had received t2-14C] ciclazindol as part of a clinical pharmacokinetic study, the results of which have already been published (Swaisland, Franklin, Southgate & Coleman, 1977). Metabolites were extracted from the first-day urines using Amberlite XAD-2 resin. Chromatography was carried out using silica gel thin layers (Kontes
Br. J. clin. Pharmac. (I 9 7 9), 7
LETTERS TO THE EDITORS
121
Im
Cl ~ /S - OH
Ciclazindol 'Metabolite
N
m'
II
\~N I
Wy 23973 Metablite fb
v
N'OH OO H
S \/
0S
N(CH2)2COOH
N\ H
~~Metabolite Ba
(CH93NH2
'I?
Cl -
OH o
Wy 24773 Metabolite IV
(CH2)2COOH Figure 1 Metabolism of ciclazindol in man. *The structure shown for metabolite Ila is that of N-(3-m-
chlorophenyl-3-hydroxy-3H-indol-2-yl)- 3-aminopropionic acid.
®
Origin
®
© Solvent front
Figure 2 Thin layer chromatographic separation of urinary metabolites of ciclazindol. XAD-2 extracts of urine were chromatographed on silica gel thin layers developed in chloroform-acetone-acetic acidwater (60:20:20:5). Roman numerals indicate the system of nomenclature used in the text. A - position of Wy 23973; B - position of ciclazindol; C-position of Wy 24773.
action of diazomethane on Wy 24773 and the product of reaction ofmetabolite IV with diazomethane were indistinguishable in CAAW (RF 0.73), TEA (RF 0.47), toluene-ethanol-acetic acid (80:20:5) (RF 0.49) and chloroform-acetone-NH40H (sp. gr. 0.880)
(60:20:1)(RFO.43).
Quantum) developed mainly in chloroform-acetone -acetic acid-water (60:20:20:5, CAAW) or in toluene-ethanol-NH40H (sp. gr. 0.880) (80:20:1, TEA). The peaks of radioactivity resulting from the separation of the metabolites in CAAW were numbered as shown in Figure 2. The position of unchanged ciclazindol and Wy 23973 (see Figure 1), a compound produced by the action of mild alkali on ciclazindol, are also shown. Table 1 shows the RF values of the metabolites and some synthetic derivatives of ciclazindol in CAAW and TEA. Extraction of the urine with toluene under basic conditions removed a substance which was chromatographically indistinguishable from ciclazindol in both CAAW and TEA. Furthermore, the ultraviolet spectrum of this material was very similar to that of authentic ciclazindol (Figure 3a). Under acidic conditions toluene extracted a compound with the chromatographic properties of metabolite IV. This indication that an acidic metabolite was produced prompted comparative studies with Wy 24773 (see Figure 1), a carboxylic acid that could arise by oxidative deamination of Wy 23973. This acid was found to have similar chromatographic characteristics to metabolite IV both in CAAW and in TEA. Furthermore, the methyl ester produced by the
Metabolite II was chromatographically similar to Wy 23973 in CAAW, but when this band was eluted and chromatographed in TEA, two components were separated. These were designated Ila and Ilb. Metabolite Ilb had a similar RF to Wy 23973 in TEA. Furthermore, the ultraviolet spectrum of metabolite llb was similar to that of authentic Wy 23973 (Figure 3b). Table 1 RF values for metabolites and derivatives of ciclazindol in CAAW and TEA
RF CAA W Metabolite 11
Ill lV V
Ciclazindol Wy 23973 Wy 24773
0.03 0.66 0.78 0.85 0.95 0.78 0.66 0.85
values
TEA
(a) 0.08 (b) 0.29 0.68 0.08 +
0.68 0.29 0.08
+ The thin layer chromatography of these fractions was not investigated in this solvent system.
122
LETTERS TO THE EDITORS
a
Br. J. clin. Pharmac. (I 9 79), 7
b
c
5)
(i) .0
.0U)
A
2 240 2 3 240 280 340 .
200
..
I
.
220
.
I .
..
260 300 340
0
200
.
(ii)
2
. . 3 3.4
240
300 340
Wavelength (nm) Figure 3 (a) Ultraviolet spectra of (i) ciclazindol from human urine and (ii) authentic ciclazindol; (b) Ultraviolet spectra of (i) metabolite lIb from human urine and (ii) authentic Wy 23973; (c) Ultraviolet spectra of (i) metabolite Ila from human urine and (ii) N-(3-m-chlorophenyl-3-hydroxy-3H-indol-2-yl)-3-aminopropionic acid.
Figure 4 Structure of Wy 24192, the alcohol related to N-(3-m-chlorophenyl-3-hydroxy-3H-indol2-yl)-3-aminopropionic acid (metabolite Ila).
Metabolite Ila had a relatively distinctive u.v. spec(Figure 3c) which was similar to that of Wy 24192, an alcohol that could have arisen from ciclazindol by cleavage of the tetrahydropyrimidine ring between C4 and the indole nitrogen (Figure 4). However, it was clear from the t.l.c. behaviour that metabolite Ila was not Wy 24192, the low mobility of the metabolite in TIRA suggesting that it was acidic. The corresponding carboxylic acid derivative of Wy 24192 was synthesized and was found to be chromatographically indistinguishable from metabolite Ila both in CAAW and in TEA. Moreover, the methyl ester of the synthetic material produced by reaction with methanol in the presence of BF3 and the product of reaction of metabolite Ila with the same reagent were chromatographically identical in CAAW (RF trum
0.55), propan-2-ol-NH4OH (sp. gr. 0.880) (8:2) (RF 0.41), toluene-ethylformate-formic acid (5:4:1) (RF 0.12) and ethanol-methanol-diethylamine (65:10:5) (RF 0.57). The ultraviolet spectrum of metabolite IIa was also very similar to that of the authentic material (Figure 3c). Attempts were made to elucidate the nature of 'metabolite 1', material remaining on the origin, with various hydrolytic treatments. Incubation with 2M HCI resulted in a decrease of this material and an increase in ciclazindol, suggesting the presence of an acid-labile conjugate of the drug. The nature of this conjugate has not been further investigated. An increase in the proportion metabolito hIa apparently at the expense of ciclazindol in those incubations where alkaline buffers were used lends support to the assumption that metabolite Ila was Wy 23973, since ciclazindol is known to degrade to this compound under alkaline conditions. All of the metabolites that have been identified have been subjected to pharmacological and toxicological tests and all were less active than the parent compound. In conclusion, therefore, it appears that all the major urinary metabolites of ciclazindol arise from biotransformations of the tetrahydropyrimidine ring (Figure 1). This observation suggests that the metabolism of ciclazindol is similar to the structurally related mazindol, where metabolism in the rat was apparently exclusive to the imidazole ring (Dugger, Coombs, Schwartz, Migdalof & Orwig, 1976). A.J. SWAISLAND, R.A. FRANKLIN & A.C. WHITE Wyeth Laboratories, Taplow, Maidenhead, Berks. Received September 19, 1978
Br. J. clin. Pharmac. (1979), 7
References DUGGER, H.A., COOMBS, R.A., SCHWARTZ, H.J.,
MIGDALOF, B.H. & ORWIG, B.A. (1976). Biotransformation of Mazindol: I. Isolation and identification of some metabolites from rat urine. Drug Metab. Dispos., 4, 262-268.
LETTERS TO THE EDITORS
123
SWAISLAND, A.J., FRANKLIN, R.A., SOUTHGATE, P.J. & COLEMAN, A.J. (1977). The pharmacokinetics of ciclazindol (Wy 23409) in human volunteers. Br. J. cin. Pharmac., 4,61-65.
THE ROLE OF THE CLINICAL PHARMACOLOGIST IN DISTRICT GENERAL HOSPITALS
The criticism made by Fullerton & Noyce (1978) of your excellent statement (British Journal of Clinical Pharmacology, 1978) on this subject highlights two major issues: first, it rehearses most of the prejudices and misconceptions surrounding clinical pharmacology; and secondly, it shows with abundant clarity the direction from which the discipline can expect least support. The basis of Fullerton & Noyce's (1978) attack comes from their assertion that clinical pharmacology ', . . is a research-based discipline rather than practisebased'. They obviously do not know that undergraduate medical students are expected to pass examinations in this subject before they can practise medicine; that it is a recognized specialty within the National Health Service; that it has its own Specialty Advisory Committee within the Joint Committee on Higher Medical Training; and that many consultants, senior registrars and registrars are in post throughout the country. Your correspondents are obviously unaware that there are patients whose clinical problems are pharmacological in nature, and who benefit from the services of a specialist clinical pharmacologist. He parallels, precisely, the physician with an organ-based specialty such as cardiology, nephrology or gastroenterology (Rawlins, 1978). The suggestion that most of the functions of a District General Hospital clinical pharmacologist can be undertaken by pharmacists is laughable. The training of a pharmacist includes little physiology, pathology or clinical medicine, and it is naive to believe that experience in hospital pharmacies provides anything more than familiarity with medical terminology. Without the clinical training which a clinical pharmacologist obtains as an undergraduate (3 years), pre-registration house officer (1 year), during general professional training (3 years), and higher medical training (4 years), the successful application of modern pharmacology to the treatment of disease is impossible. The notion that clinical pharmacology should be
subjected to 'careful appraisal' is one which several of us have considered. Although it would be simple to analyse a clinical pharmacologist's working pattern, it would be much more difficult to assess 'benefit' (either positive or negative). Really useful information-such as his influence on the incidence of adverse drug reactions in his hospital and his community-would be so expensive to gather as to negate the exercise completely. Perhaps this is why Drug Information Services, of which Fullerton & Noyce (1978) speak so highly, have not been subjected to detailed cost-benefit analysis. Finally, Fullerton & Noyce (1978) are possibly unaware that the concept of DGH clinical pharmacologists originated-from the Royal College of Physicians (1974). Their suggestion that clinical pharmacologists have supported the scheme merely to expand their discipline is as insulting as it is inaccurate. M.D. RAWLINS Department of Pharmacological Sciences, Wolfson Unit of Clinical Pharmacology, University of Newcastle upon Tyne, Newcastle upon Tyne Received September 19, 1978
References BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
(1978). The role of the clinical pharmacologist in district general hospitals. Br. J. clin. Pharmac., 5, 3-5. FULLERTON, S.E. & NOYCE, P.R. (1978). The role of the clinical pharmacologist in district general hospitals. Br. J. clin. Pharmac., 6, 180-181. RAWLINS, M.D. (1978). Clinical Pharmacology in the National Health Service. J. Roy. Soc. Med., 71, 556-557. ROYAL COLLEGE OF PHYSICIANS (1974). Report of the Committee on Clinical Pharmacology. London: Royal College of Physicians.
