LETTERS TO THE EDITORS
would indicate the presence of a second and longer elimination half life. Any accurate assessment of this longer half life could not be made due to the lack of information between the 8 and 24 h samples. It is clear from this study that the proposed method is capable of simply estimating plasma levels over an extended period after a single oral dose of this drug.
339
D.J. WITTS Department of Clinical Pharmacology, St Bartholomews. Hospital, London ECIA 7BE Received October 29, 1975
The authors wish to thank Professor P. Turner for his encouragement and the use of facilities to carry out the work and to Ayerst Laboratories for samples of tandamine hydrochloride.
References
L.A. GIFFORD
GIFFORD, L.A., TURNER, P. & PARE, C.M.B. (1975).
Department of Chemistry, Loughborough University of Technology, Loughborough, Leicester LEII 3TU
AYERST RESEARCH LABORATORIES. Reports, Animal Health Division.
Internal
Sensitive method for the routine determination of tricyclic antidepressants in plasma using a specific nitrogen detectorJ. Chromatogr., 105, 107-113.
RECTAL ADMINISTRATION OF FEPRAZONE IN HEALTHY VOLUNTEERS Drugs given rectally in the form of suppositories are used for local therapy, for systemic effects or for situations in which the oral route is unsatisfactory. Dissolution of drug from a suppository may be the rate-limiting step for the overall absorption process and therefore particle size and suppositories formulations become significant factors affecting the absorption rate. The purpose of the study was to compare the bioavailability of the feprazone (4 - prenyl - 1,2 - diphenyl - 3,5 pyrazolidinedione), effective drug in rheumatoid arthritis (Cherie Ligniere, Colombo, Carabba, Ferrari & Robotti, 1972; Billings, Burry, Grahame & Berry, 1975; Fletcher, Loebl & Scott, 1975; Sturrock, Isaacs & Hart, 1975), after rectal administration of three lots of suppositories with different formulations of the base and different particle size. Six healthy volunteers (three males and three females ranging in age from 21-25 years and in body weight from 50-82 kg) entered the trial after their informed consent. The volunteers had not consumed any drug substances for at least one week prior to suppositories administration and during the study itself. All subjects were fasted ovemight and 4 h post dosing. No enema was given before drug administration. The subjects received suppositories containing feprazone (300 mg). The code of treatment, the suppositories base and particle size are respectively: A = Witepsol
(1390 mg), soya lecithin (5.7 mg) and particle size 18.4 ,u; B = Suppocire BML (1400 mg) and particle size 18.4,u; C= Suppocire BML (1520 mg) and particle size 8.8 ,u. The study has been planned as balanced incomplete block design (Li, 1964). Each subject received two of the three treatments on two different occasions with a wash-out period of 7 days between administrations. Blood samples (10 ml) were drawn from each subject at 3, 6, 9, 24, 27, 32 h after insertion of the suppository. The samples were centrifuged as soon as possible after collection and the serum samples were assayed using a specific gas-chromatographic method (Perego, Gallazzi, Vanoni & Lucarella, 1972). The mean serum levels of feprazone for each of three formulations are in Figure 1. The first step of data analysis is carried out on the area under serum levels, on the peak height of the serum levels and on the time to reach the peak, which are generally considered as parameters describing bioavailability (Ritschel, 1972). The differences in the bioavailability parameters among the three formulations are not statistically significant. On the other hand the figure shows the possibility that the formulation A might have a serum levels pattem different from those of the formulations B and C. The second step of data analysis is to compare the shape of the three serum level patterns. The outcome of the analysis of variance for testing these differences (Westlake,
LETTERS TO THE EDITORS
340
treatment of patients with rheumatoid arthritis and allied clinical conditions.
E 15
0)
12
P. FERRARI, C. MONTANARI, P. SALA AND A. VIDI Department of Clinical Pharmacology, Istituto De Angeli-S.p.A., Via Serio, 15, 20139 Milan, Italy
3
0 c
Received August 7, 1975
6) References
BILLINGS, R., BURRY, H.C., GRAHAME, R., BERRY, D.J. & DONOVAN, B. (1975). A double-blind cross=1
CD
3
6
9
12
15
18 21 24 27 30 33
Time (h)
Figure 1 Mean (± s.e. mean) serum concentrations of feprazone following rectal administration of feprazone (300 mg) as three different suppository formulations (A = A; 0 = B;. = C).
1974) shows that the interaction (times of sampling x formulations) is statistically significant, P < 0.025, and that formulation A is different from formulations B and C or in other words the profiles of the three feprazone curves are not parallel, especially in the early phase of absorption. This difference is not correlated with the particle size but seems to be influenced by suppository formulation. This mild but statistical difference in pattern cannot be considered important from the clinical point of view. In fact it is debatable whether it is possible to obtain different steady state serum levels after multiple dose and consequently different therapeutic availability in the long term
over trial of prenazone and aspirin in the management of rheumatoid arthritis. Rheumat. Rehab., 14, 61-66. CHERIE LIGNIERE, G., COLOMBO, B., CARABBA, M.,
FERRARI, P. & ROBOTTI, E. (1972). Clinical and laboratory evaluation of 4 - prenyl - 1,2 - diphenyl 3,5 - pyrazolidinedione (DA 2370) in rheumatoid arthritis and ankylosing spondylitis. Arzneimittelforsch., 22, 253-258. FLETCHER, M.R., LOEBL, W. & SCOTT, J.T.(1975). Feprazone a new anti-inflammatory agent: studies of potency and gastrointestinal tolerance. Ann. Rheum. Dis., 34, 190-194. LI, C.C. (1964). Introduction to experimental statistics, pp. 362-379. New York and London: McGraw-Hill. PEREGO, R., GALLAZZI, A., VANONI, P.C. & LUCARELLA, I. (1972). Physico-chemical and analytical studies on 4 - prenyl - 1,2 - diphenyl - 3,5 -
pyrazolidinedione (DA 2370). Arzneimittel-forsch., 22, 177-183. RITSCHEL, W.A. (1972). Bioavailability in the clinical evaluation of drugs. Drug. Intell. Clin. Pharm., 6, 246-256. STURROCK,
R.,
ISAACS,
A.
&
HART,
F.D.
(1975). Feprazone compared with indomethacin in the management of rheumatoid arthritis. Practitioner, 215, 94-97. WESTLAKE, W.J. (1974). The use of balanced incomplete block designs in comparative bioavailability trials. Biometrics, 30, 319-327.
would indicate the presence of a second and longer elimination half life. Any accurate assessment of this longer half life could not be made due to the lack of information between the 8 and 24 h samples. It is clear from this study that the proposed method is capable of simply estimating plasma levels over an extended period after a single oral dose of this drug.
339
D.J. WITTS Department of Clinical Pharmacology, St Bartholomews. Hospital, London ECIA 7BE Received October 29, 1975
The authors wish to thank Professor P. Turner for his encouragement and the use of facilities to carry out the work and to Ayerst Laboratories for samples of tandamine hydrochloride.
References
L.A. GIFFORD
GIFFORD, L.A., TURNER, P. & PARE, C.M.B. (1975).
Department of Chemistry, Loughborough University of Technology, Loughborough, Leicester LEII 3TU
AYERST RESEARCH LABORATORIES. Reports, Animal Health Division.
Internal
Sensitive method for the routine determination of tricyclic antidepressants in plasma using a specific nitrogen detectorJ. Chromatogr., 105, 107-113.
RECTAL ADMINISTRATION OF FEPRAZONE IN HEALTHY VOLUNTEERS Drugs given rectally in the form of suppositories are used for local therapy, for systemic effects or for situations in which the oral route is unsatisfactory. Dissolution of drug from a suppository may be the rate-limiting step for the overall absorption process and therefore particle size and suppositories formulations become significant factors affecting the absorption rate. The purpose of the study was to compare the bioavailability of the feprazone (4 - prenyl - 1,2 - diphenyl - 3,5 pyrazolidinedione), effective drug in rheumatoid arthritis (Cherie Ligniere, Colombo, Carabba, Ferrari & Robotti, 1972; Billings, Burry, Grahame & Berry, 1975; Fletcher, Loebl & Scott, 1975; Sturrock, Isaacs & Hart, 1975), after rectal administration of three lots of suppositories with different formulations of the base and different particle size. Six healthy volunteers (three males and three females ranging in age from 21-25 years and in body weight from 50-82 kg) entered the trial after their informed consent. The volunteers had not consumed any drug substances for at least one week prior to suppositories administration and during the study itself. All subjects were fasted ovemight and 4 h post dosing. No enema was given before drug administration. The subjects received suppositories containing feprazone (300 mg). The code of treatment, the suppositories base and particle size are respectively: A = Witepsol
(1390 mg), soya lecithin (5.7 mg) and particle size 18.4 ,u; B = Suppocire BML (1400 mg) and particle size 18.4,u; C= Suppocire BML (1520 mg) and particle size 8.8 ,u. The study has been planned as balanced incomplete block design (Li, 1964). Each subject received two of the three treatments on two different occasions with a wash-out period of 7 days between administrations. Blood samples (10 ml) were drawn from each subject at 3, 6, 9, 24, 27, 32 h after insertion of the suppository. The samples were centrifuged as soon as possible after collection and the serum samples were assayed using a specific gas-chromatographic method (Perego, Gallazzi, Vanoni & Lucarella, 1972). The mean serum levels of feprazone for each of three formulations are in Figure 1. The first step of data analysis is carried out on the area under serum levels, on the peak height of the serum levels and on the time to reach the peak, which are generally considered as parameters describing bioavailability (Ritschel, 1972). The differences in the bioavailability parameters among the three formulations are not statistically significant. On the other hand the figure shows the possibility that the formulation A might have a serum levels pattem different from those of the formulations B and C. The second step of data analysis is to compare the shape of the three serum level patterns. The outcome of the analysis of variance for testing these differences (Westlake,
LETTERS TO THE EDITORS
340
treatment of patients with rheumatoid arthritis and allied clinical conditions.
E 15
0)
12
P. FERRARI, C. MONTANARI, P. SALA AND A. VIDI Department of Clinical Pharmacology, Istituto De Angeli-S.p.A., Via Serio, 15, 20139 Milan, Italy
3
0 c
Received August 7, 1975
6) References
BILLINGS, R., BURRY, H.C., GRAHAME, R., BERRY, D.J. & DONOVAN, B. (1975). A double-blind cross=1
CD
3
6
9
12
15
18 21 24 27 30 33
Time (h)
Figure 1 Mean (± s.e. mean) serum concentrations of feprazone following rectal administration of feprazone (300 mg) as three different suppository formulations (A = A; 0 = B;. = C).
1974) shows that the interaction (times of sampling x formulations) is statistically significant, P < 0.025, and that formulation A is different from formulations B and C or in other words the profiles of the three feprazone curves are not parallel, especially in the early phase of absorption. This difference is not correlated with the particle size but seems to be influenced by suppository formulation. This mild but statistical difference in pattern cannot be considered important from the clinical point of view. In fact it is debatable whether it is possible to obtain different steady state serum levels after multiple dose and consequently different therapeutic availability in the long term
over trial of prenazone and aspirin in the management of rheumatoid arthritis. Rheumat. Rehab., 14, 61-66. CHERIE LIGNIERE, G., COLOMBO, B., CARABBA, M.,
FERRARI, P. & ROBOTTI, E. (1972). Clinical and laboratory evaluation of 4 - prenyl - 1,2 - diphenyl 3,5 - pyrazolidinedione (DA 2370) in rheumatoid arthritis and ankylosing spondylitis. Arzneimittelforsch., 22, 253-258. FLETCHER, M.R., LOEBL, W. & SCOTT, J.T.(1975). Feprazone a new anti-inflammatory agent: studies of potency and gastrointestinal tolerance. Ann. Rheum. Dis., 34, 190-194. LI, C.C. (1964). Introduction to experimental statistics, pp. 362-379. New York and London: McGraw-Hill. PEREGO, R., GALLAZZI, A., VANONI, P.C. & LUCARELLA, I. (1972). Physico-chemical and analytical studies on 4 - prenyl - 1,2 - diphenyl - 3,5 -
pyrazolidinedione (DA 2370). Arzneimittel-forsch., 22, 177-183. RITSCHEL, W.A. (1972). Bioavailability in the clinical evaluation of drugs. Drug. Intell. Clin. Pharm., 6, 246-256. STURROCK,
R.,
ISAACS,
A.
&
HART,
F.D.
(1975). Feprazone compared with indomethacin in the management of rheumatoid arthritis. Practitioner, 215, 94-97. WESTLAKE, W.J. (1974). The use of balanced incomplete block designs in comparative bioavailability trials. Biometrics, 30, 319-327.
