Br. J. clin. Pharmac. (1992), 33, 449-450
Pharmacokinetics of dipipanone after a single oral dose SUSAN PATERSON Department Forensic Medicine and Toxicology, Charing Cross and Westminster Medical School, St Dunstan's Road, London W6
A single oral dose of Diconal (dipipanone HCI 10
mg,
cyclizine HCI 30 mg)
was
given
to six volunteers. The mean peak plasma dipipanone concentration was 29 ng ml-', the time to peak plasma concentration was 1-2 h, the mean elimination half-life was 3.5 h
and the mean AUC was 156 ng ml-1 min. Less than 1% of the dose was excreted in urine unchanged over 24 h. Keywords
pharmacokinetics
dipipanone
Introduction Dipipanone is only available in Britain combined with cyclizine in the preparation Diconal (dipipanone hydrochloride 10 mg, cyclizine hydrochloride 30 mg). Diconal has been in clinical use since the 1950s and abused by addicts since the early 1970s although it is currently much less favoured as a drug of abuse than it was in the late 1980s. Even though Diconal has been available for 30 years, only one other pharmacokinetic study of dipipanone has been reported (Cathapermal & Caddy, 1987). This was also a single dose oral study but only three volunteers were used, no urine measurements were made and blood samples were collected for 6 h only. Presented here are the results from a single oral dose study on six volunteers in which blood and urine were collected for 24 h.
and 24 h. The plasma was removed and stored at -20° C until analysed. Each time urine was passed during the 24 h the volume was measured and 20 ml retained for analysis. Urine was also stored at -20° C. Urine flow rate and pH were not controlled. Dipipanone was measured using solid phase extraction and capillary gas chromatography (Paterson, 1988). The limit of assay for dipipanone in both plasma and urine was 5 ng ml-'. Samples were measured in duplicate where possible and results were accepted only if they differed by less than 10%.
Results The urine recovery of unchanged dipipanone over 24 h varied between 0.38 and 1.16% (mean = 0.75, 95% CI, 0.53-0.97, n = 6) of the given dose. Figure 1 shows the mean (± s.d.) plasma concentrations of dipipanone. The drug was not detected in any of the plasma samples taken at 20 min or at 24 h. The peak plasma dipipanone concentration varied between 18 and 41 ng ml- (mean = 29, 95% CI, 23-36, n = 6) and was reached at 1-2 h post dose. The elimination half-life varies between 3.2 and 3.8 h (mean = 3.5, 95% CI, 3.3-3.7, n = 6). The area under the curve calculated using the linear trapezoidal method, was 156 ng ml-' (95% CI, 122-191, n = 6).
Methods
The study was approved by the Charing Cross and Westminster Medical School ethics committee and the volunteers gave written consent. After fasting overnight, a single oral dose of Diconal (10 mg dipipanone hydrochloride, 30 mg cyclizine hydrochloride) was given to six healthy volunteers who were members of the laboratory staff (two men, four women), their ages ranged from 21 to 35 years and their weight from 51 to 86 kg. The hepatic and renal function of the subjects was not measured but none had any known impairment. The subjects swallowed the tablet whole with water (100 ml) and remained seated for the next 2 h. They then ate a light breakfast and afterwards resumed their normal duties. Food and fluid was taken as normal throughout the rest of the day. Blood samples were collected at 20 and 40 min and at 1, 1.5, 2, 4, 6, 8,
Discussion
This investigation was initiated because Diconal was being increasingly abused by drug addicts and was causing an increasing number of deaths among this population.
Correspondence: Dr S. Paterson, Department Forensic Medicine and Toxicology, Charing Cross and Westminster Medical School, St Dunstan's Road, London W6
449
450
Susan Paterson 100 _
E
m
° 10 0
0. Cu
-n
1
0
II
2
4
6
8
Time (h) Figure 1 Mean (± s.d.) plasma dipipanone concentrations after a 10 mg dose of dipipanone HCI (given as Diconal tablets). (n = 6).
However, there were no pharmacokinetic data in the literature for dipipanone and, therefore, no way of interpreting whether the concentrations of dipipanone found in post-mortem samples were therapeutic or
potentially fatal. Also, the ability to establish the length of time a drug can be detected in urine or plasma is essential in medico-legal work. Both plasma and urine concentrations of dipipanone were low. The plasma concentrations were much lower than those reported by Cathapermal & Caddy (1987) who found a maximum of between 212 and 276 ng ml- 1. Although it is possible that cyclizine influences the kinetics of dipipanone it seems unlikely since the dose of cyclizine is small and the low plasma concentrations of dipipanone suggest that it is cleared rapidly. Dipipanone is always given in combination with cyclizine and therefore it was appropriate to give Diconal rather than dipipanone alone to the volunteers. More precise pharmacokinetic parameters can be obtained following an intravenous dose. This was precluded by ethical considerations as dipipanone causes an alarming fall in blood pressure on intravenous administration (Pharmaceutical Codex, 1979). Attempts to extend the study to include measurements from patients on chronic dipipanone therapy were unsuccessful owing to the inability to locate such patients even though requests were made in the medical press.
References Cathapermal, S. & Caddy, B. (1987). The analysis and disposition of Diconal. In Proceedings of 11th meeting of International Association of Forensic Sciences. Vancouver: International Association of Forensic Sciences. Paterson, S. (1988). Measurement of dipipanone using capillary
chromatography. J. Chromatogr., 424, 152-157. The Pharmaceutical Codex (1979). 11th Edition. London: The Pharmaceutical Press.
(Received 19 July 1991, accepted 16 December 1991)
Pharmacokinetics of dipipanone after a single oral dose SUSAN PATERSON Department Forensic Medicine and Toxicology, Charing Cross and Westminster Medical School, St Dunstan's Road, London W6
A single oral dose of Diconal (dipipanone HCI 10
mg,
cyclizine HCI 30 mg)
was
given
to six volunteers. The mean peak plasma dipipanone concentration was 29 ng ml-', the time to peak plasma concentration was 1-2 h, the mean elimination half-life was 3.5 h
and the mean AUC was 156 ng ml-1 min. Less than 1% of the dose was excreted in urine unchanged over 24 h. Keywords
pharmacokinetics
dipipanone
Introduction Dipipanone is only available in Britain combined with cyclizine in the preparation Diconal (dipipanone hydrochloride 10 mg, cyclizine hydrochloride 30 mg). Diconal has been in clinical use since the 1950s and abused by addicts since the early 1970s although it is currently much less favoured as a drug of abuse than it was in the late 1980s. Even though Diconal has been available for 30 years, only one other pharmacokinetic study of dipipanone has been reported (Cathapermal & Caddy, 1987). This was also a single dose oral study but only three volunteers were used, no urine measurements were made and blood samples were collected for 6 h only. Presented here are the results from a single oral dose study on six volunteers in which blood and urine were collected for 24 h.
and 24 h. The plasma was removed and stored at -20° C until analysed. Each time urine was passed during the 24 h the volume was measured and 20 ml retained for analysis. Urine was also stored at -20° C. Urine flow rate and pH were not controlled. Dipipanone was measured using solid phase extraction and capillary gas chromatography (Paterson, 1988). The limit of assay for dipipanone in both plasma and urine was 5 ng ml-'. Samples were measured in duplicate where possible and results were accepted only if they differed by less than 10%.
Results The urine recovery of unchanged dipipanone over 24 h varied between 0.38 and 1.16% (mean = 0.75, 95% CI, 0.53-0.97, n = 6) of the given dose. Figure 1 shows the mean (± s.d.) plasma concentrations of dipipanone. The drug was not detected in any of the plasma samples taken at 20 min or at 24 h. The peak plasma dipipanone concentration varied between 18 and 41 ng ml- (mean = 29, 95% CI, 23-36, n = 6) and was reached at 1-2 h post dose. The elimination half-life varies between 3.2 and 3.8 h (mean = 3.5, 95% CI, 3.3-3.7, n = 6). The area under the curve calculated using the linear trapezoidal method, was 156 ng ml-' (95% CI, 122-191, n = 6).
Methods
The study was approved by the Charing Cross and Westminster Medical School ethics committee and the volunteers gave written consent. After fasting overnight, a single oral dose of Diconal (10 mg dipipanone hydrochloride, 30 mg cyclizine hydrochloride) was given to six healthy volunteers who were members of the laboratory staff (two men, four women), their ages ranged from 21 to 35 years and their weight from 51 to 86 kg. The hepatic and renal function of the subjects was not measured but none had any known impairment. The subjects swallowed the tablet whole with water (100 ml) and remained seated for the next 2 h. They then ate a light breakfast and afterwards resumed their normal duties. Food and fluid was taken as normal throughout the rest of the day. Blood samples were collected at 20 and 40 min and at 1, 1.5, 2, 4, 6, 8,
Discussion
This investigation was initiated because Diconal was being increasingly abused by drug addicts and was causing an increasing number of deaths among this population.
Correspondence: Dr S. Paterson, Department Forensic Medicine and Toxicology, Charing Cross and Westminster Medical School, St Dunstan's Road, London W6
449
450
Susan Paterson 100 _
E
m
° 10 0
0. Cu
-n
1
0
II
2
4
6
8
Time (h) Figure 1 Mean (± s.d.) plasma dipipanone concentrations after a 10 mg dose of dipipanone HCI (given as Diconal tablets). (n = 6).
However, there were no pharmacokinetic data in the literature for dipipanone and, therefore, no way of interpreting whether the concentrations of dipipanone found in post-mortem samples were therapeutic or
potentially fatal. Also, the ability to establish the length of time a drug can be detected in urine or plasma is essential in medico-legal work. Both plasma and urine concentrations of dipipanone were low. The plasma concentrations were much lower than those reported by Cathapermal & Caddy (1987) who found a maximum of between 212 and 276 ng ml- 1. Although it is possible that cyclizine influences the kinetics of dipipanone it seems unlikely since the dose of cyclizine is small and the low plasma concentrations of dipipanone suggest that it is cleared rapidly. Dipipanone is always given in combination with cyclizine and therefore it was appropriate to give Diconal rather than dipipanone alone to the volunteers. More precise pharmacokinetic parameters can be obtained following an intravenous dose. This was precluded by ethical considerations as dipipanone causes an alarming fall in blood pressure on intravenous administration (Pharmaceutical Codex, 1979). Attempts to extend the study to include measurements from patients on chronic dipipanone therapy were unsuccessful owing to the inability to locate such patients even though requests were made in the medical press.
References Cathapermal, S. & Caddy, B. (1987). The analysis and disposition of Diconal. In Proceedings of 11th meeting of International Association of Forensic Sciences. Vancouver: International Association of Forensic Sciences. Paterson, S. (1988). Measurement of dipipanone using capillary
chromatography. J. Chromatogr., 424, 152-157. The Pharmaceutical Codex (1979). 11th Edition. London: The Pharmaceutical Press.
(Received 19 July 1991, accepted 16 December 1991)
