- Email: [email protected]
AVAILABILITY OF THREE ANTIBIOTICS AFTER INTRAMUSCULAR INJECTION INTO THIGH AND BUTTOCK
1421
the lungs, are compatible with, and add more weight to, this hypothesis. However, more detailed studies are necessary to establish a pathophysiological role of P.G.Fza in bronchial asthma. Such studies are in progress in our
Ciba-Geigy) we noted that the peak serum levels of the drug varied according to the site of intraFurther investigations of this muscular injection. observation were done using three antibiotics-cephacetrile, cephaloridine, and gentamicin.
laboratories. This
study
was
(project no. 03X-217) to Prof. B. Samuelsson. Requests for reprints shoud be addressed to P. H., Department of Physiology, Karolinska Institute, S-104 01 Stockholm 60, Sweden. REFERENCES 1. Änggård, E. Biochem. Pharmac. 1965, 14, 1507. 2. Piper, P. J., Walker, J. L. Br. J. Pharmac. 1973, 47, 291. 3. Sweatman, W. J. F., Collier, H. O. J. Nature, 1968, 217, 69. 4. Hedqvist, P., Holmgren, A., Mathé, A. A. Acta physiol. scand. 1971, 82, 29 abstr. 5. Horton, E. W. Physiol. Rev. 1969, 49, 122. 6. Mathé, A. A., Hedqvist, P., Holmgren, A., Svanborg, N. Br. med. J. 1973, i, 193. 7. Gréen, K., Granström, E., Samuelsson, B., Axén, U. Analyt. Biochem. 1973, 55, 368. 8. Gréen, K., Samuelsson, B. Biochem. Med. (in the press). 9. Granström, E. Eur. J. Biochem. 1972, 27, 462. 10. Samuelsson, B. Adv. Biosci. 1973, 9, 7. 11. Gréen, K., Bygdeman, M., Toppozada, M., Wiqvist, N. Am. J. Obstet. Gynec. 1974, 120, 25. 12. Svanborg, N., Hamberg, M., Hedqvist, P. Acta physiol. scand.
1973, 89, suppl. 396, p. 101. Strandberg, K., Hamberg, M. Prostaglandins, 1974, 6, 159. Kopeloff, N., Kopeloff, L. M. J. Immun. 1941, 40, 471. 15. Johansson, S. A. Acta physiol. scand. 1960, 50, 95. 16. Pegelow, K. O. Acta allergol. 1968, 23, 287. 17. Hamberg, M. Biochem. Biophys. Res. Comm. 1972, 49, 720. 13. 14.
levels
of
cephacetrile, gentamicin were
apparent after intramuscular differences were not significant. Serum levels of cephaloridine showed no significant differences, but urinary recovery of drug was significantly greater after thigh injection. was
gentamicin, although the
INTRODUCTION
WHILE assessing pharmacologically in antibiotic cephacetrile
*
Present address: Department of Medical
Hospital, Birmingham.
man
were
Laboratory
Procedures and urine
samples were assayed using direct plate-diffusion microbiological methods. Cephacetrile was assayed employing a Bacillus subtilis spore suspension in The
serum
±15%.
cephaloridine, and healthy volunteers after intramuscular thigh and buttock sites. There were significantly higher peak serum levels of the cephacetrile after thigh injection (vastus lateralis) when compared to a buttock injection (gluteus maximus).
cephalosporin
before and at 15, 30, 45, 60, 120, 240, 360, and 480 minutes after injection. All urine was collected for 8 hours after injection in 2-hour samples.
Difco ’Penassay’ agar: this method could detect less than 0’3 jug. per ml. Cephaloridine was assayed using a B. subtilis spore suspension in Difco penassay agar: the lower limit of measurement was 0’2 jug. per ml. The gentamicin assay used a B. pumilis spore with Difco no. 5 agar and could detect less than 0’05 jug. per ml. The confidence limits of 95 % of these assays were all better than
measured in injection into
A similar trend
Nine male and one female volunteers were given 500 mg. cephaloridine (’Ceporin’, Glaxo) in 2 ml. of saline. The sites used were as for cephacetrile. Blood was collected
given 80 2 ml. into the two sites. Serum samples were taken before the dose and at 10, 20, 30, 40, 50, 60, 120, 240, 360, and 480 minutes afterwards. Urine was collected as for cephacetrile.
Laboratories, Horsham, Sussex serum
Cephaloridine
Eight male and one female volunteers gentamicin (’Genticin’, Nicholas) in
V. B. WHITMARSH
The
two females, all of whom had normal renal function (creatinine clearance > 100 ml. per minute), received 1 g. cephacetrile dissolved in 2’5 ml. of 2% lignocaine. All injections were given by one person. The drug was injected into either the anterolateral aspect of the thigh or the upper outer -quadrant of the buttock. At least 48 hours later the other site was used. The physical activity of the subject was made similar for each occasion. Blood-samples were taken just before a dose and 15, 30, 45, 60, 240, 360, and 480 minutes afterwards. Urine was collected before the dose and then 0-2, 2-4, 4-6, and 6-12 hours after the drug.
mg.
D. S. REEVES M. J. BYWATER R. WISE* Department of Medical Microbiology, Southmead Hospital, Bristol BS10 5NB
Summary
Cephacetrile Ten volunteers, eight males and
Gentamicin
AVAILABILITY OF THREE ANTIBIOTICS AFTER INTRAMUSCULAR INJECTION INTO THIGH AND BUTTOCK
Ciba
METHODS
supported by grants from the Swedish
National Association against Heart and Chest Diseases, Magnus Bergvalls Stiftelse, and the Swedish Medical Research Council
the
new
(’Celospor’,
Microbiology, Dudley Road
SERUM-LEVELS ((g./ml.) AND URINE EXCRETION (mg.) AFTER INJECTION INTO THIGH OR BUTTOCK OF 1 g. CEPHACETRILE, 500
mg. CEPHALORIDINE,
OR
80 mg.
GENTAMICIN ,
1422
_
_
_
-
Hours
Fig. 1-Mean
serum
levels of cephacetrile after into thigh or buttock.
injection of 1
g.
RESULTS
Cephacetrile Both the mean serum peak levels of the drug and the time at which the peak occurred differed with the site of the injection (table, fig. 1). After thigh injection, the mean peak serum level was 3 3’3 /.g. per ml. at 30 minutes and was 24 % higher than that after buttock injection (28’5 Mg. per ml. at 45 minutes). The differences at 15 and 30 minutes (Wilcoxon signed-rank test and Student’s t test) are statistically After 2 hours the mean serum significant (p<0’05). levels after buttock injection were higher than those after thigh injection, being significantly so at 8 hours (n<0°Ol). Analysis of urinary elimination of the drug showed a significantly greater excretion in the first 6 hours after injection in the thigh (table).
Cephaloridine There were no consistent differences in cephaloridine serum levels with regard to sites of injection. Our values for serum levels were analysed mathematically by Glaxo Laboratories using a curve-fitting computer program. The results obtained resembled those without this aid, but the computer data were used in the analysis for differences between sites of injection. The mean peak serum concentration after thigh injection was 16-9 ju-g. per ml. (range 14-1-23-9) at a mean time of 46-3 minutes. The corresponding figures after buttock injection were 15’7 ttg. per ml. (range 12-3203) at 43-3 minutes. The initial absorption-rates (1-19 and 1-25 jug. per ml. per minute) and ultimate half-lives (76-8 and 81-0 minutes) were similar for the thigh and buttock injections, respectively. There was, however, a striking difference in urine excretion over the time studied (table), there being significantly more cephaloridine excreted in the urine after thigh injection than after buttock injection. Gentamicin After injection the mean peak serum-levels occurred at 30 minutes with both intramuscular sites. Although the levels at this time (table) were higher after thigh injection than buttock injection, the differences were not significantly different. The mean serum
Fig. 2-Mean serum levels of gentamicin after injection of 80 mg. into thigh or buttock.
levels of the nine volunteers are shown in fig. 2. There were no significant differences in urinary excretion over the first 6 hours after injection (table). DISCUSSION
There seem to have been remarkably few systematic investigations into the influence of intramuscular injection site on drug pharmacology apart from that of Nora et all who described a more rapid effect of insulin injected intramuscularly into the deltoid region than the thigh. So far the buttock and thigh sites have been considered synonymous. In the wards, the site is almost always determined by nursing considerations rather than by medical prescriptions, and is all too rarely defined in pharmacological studies. We do not claim that the differences described are clinically significant, but the results do indicate a lack of synonymity between the two sites that could affect the clinical performance of other drugs. The difference between the drugs investigated could be accounted for by their formulations or physical properties, since such factors as volume and concentration of injection,2osmolarity, pH,3 and additives Exercan affect absorption in animal experiments. cise plays an important role in drug absorption,1-.fi and our findings may not apply to patients in bed. Illnesses may also affect the rate of absorption,7-9 as may local conditions at site of injection." These factors require further evaluation. We thank Glaxo Laboratories Ltd. and Nicholas Laboratories Ltd. for their support. Requests for reprints should be addressed to R. W. REFERENCES
Nora, J. J., Smith, W. D., Cameron, J. R. J. Pediat. 1964, 64, 547. Sund, R. B., Schon, J. Acta pharmac. toxic. 1964, 21, 213. Cutts, J. H., Walker, I. G. Cancer Res. 1966, 26, 1386. Ballard, B. E. J. pharm. Sci. 1966, 55, 515. Barnes, J. M., Trueta, J. Lancet, 1941, i, 623. Schmidt, H., Roholt, K. Acta path. microbiol. stand. 1966, 68, 396. Bauer, F. K., Cassen, B., Youtcheff, E., Shoop, L. Am. J. med. Sct. 1953, 255, 374. 8. De Groot, L. J., Pretell, E., Garcia, M. E. New Engl. J. Med. 1966 274, 133. 9. Irons, E. M. J. Am. med. Ass. 1950, 142, 97. 10. Winters, R. E., Litwack, K. D., Hewitt, W. L. J. infect. Dis. 1971. 124, suppl. p. 90. 1. 2. 3. 4. 5. 6. 7.
the lungs, are compatible with, and add more weight to, this hypothesis. However, more detailed studies are necessary to establish a pathophysiological role of P.G.Fza in bronchial asthma. Such studies are in progress in our
Ciba-Geigy) we noted that the peak serum levels of the drug varied according to the site of intraFurther investigations of this muscular injection. observation were done using three antibiotics-cephacetrile, cephaloridine, and gentamicin.
laboratories. This
study
was
(project no. 03X-217) to Prof. B. Samuelsson. Requests for reprints shoud be addressed to P. H., Department of Physiology, Karolinska Institute, S-104 01 Stockholm 60, Sweden. REFERENCES 1. Änggård, E. Biochem. Pharmac. 1965, 14, 1507. 2. Piper, P. J., Walker, J. L. Br. J. Pharmac. 1973, 47, 291. 3. Sweatman, W. J. F., Collier, H. O. J. Nature, 1968, 217, 69. 4. Hedqvist, P., Holmgren, A., Mathé, A. A. Acta physiol. scand. 1971, 82, 29 abstr. 5. Horton, E. W. Physiol. Rev. 1969, 49, 122. 6. Mathé, A. A., Hedqvist, P., Holmgren, A., Svanborg, N. Br. med. J. 1973, i, 193. 7. Gréen, K., Granström, E., Samuelsson, B., Axén, U. Analyt. Biochem. 1973, 55, 368. 8. Gréen, K., Samuelsson, B. Biochem. Med. (in the press). 9. Granström, E. Eur. J. Biochem. 1972, 27, 462. 10. Samuelsson, B. Adv. Biosci. 1973, 9, 7. 11. Gréen, K., Bygdeman, M., Toppozada, M., Wiqvist, N. Am. J. Obstet. Gynec. 1974, 120, 25. 12. Svanborg, N., Hamberg, M., Hedqvist, P. Acta physiol. scand.
1973, 89, suppl. 396, p. 101. Strandberg, K., Hamberg, M. Prostaglandins, 1974, 6, 159. Kopeloff, N., Kopeloff, L. M. J. Immun. 1941, 40, 471. 15. Johansson, S. A. Acta physiol. scand. 1960, 50, 95. 16. Pegelow, K. O. Acta allergol. 1968, 23, 287. 17. Hamberg, M. Biochem. Biophys. Res. Comm. 1972, 49, 720. 13. 14.
levels
of
cephacetrile, gentamicin were
apparent after intramuscular differences were not significant. Serum levels of cephaloridine showed no significant differences, but urinary recovery of drug was significantly greater after thigh injection. was
gentamicin, although the
INTRODUCTION
WHILE assessing pharmacologically in antibiotic cephacetrile
*
Present address: Department of Medical
Hospital, Birmingham.
man
were
Laboratory
Procedures and urine
samples were assayed using direct plate-diffusion microbiological methods. Cephacetrile was assayed employing a Bacillus subtilis spore suspension in The
serum
±15%.
cephaloridine, and healthy volunteers after intramuscular thigh and buttock sites. There were significantly higher peak serum levels of the cephacetrile after thigh injection (vastus lateralis) when compared to a buttock injection (gluteus maximus).
cephalosporin
before and at 15, 30, 45, 60, 120, 240, 360, and 480 minutes after injection. All urine was collected for 8 hours after injection in 2-hour samples.
Difco ’Penassay’ agar: this method could detect less than 0’3 jug. per ml. Cephaloridine was assayed using a B. subtilis spore suspension in Difco penassay agar: the lower limit of measurement was 0’2 jug. per ml. The gentamicin assay used a B. pumilis spore with Difco no. 5 agar and could detect less than 0’05 jug. per ml. The confidence limits of 95 % of these assays were all better than
measured in injection into
A similar trend
Nine male and one female volunteers were given 500 mg. cephaloridine (’Ceporin’, Glaxo) in 2 ml. of saline. The sites used were as for cephacetrile. Blood was collected
given 80 2 ml. into the two sites. Serum samples were taken before the dose and at 10, 20, 30, 40, 50, 60, 120, 240, 360, and 480 minutes afterwards. Urine was collected as for cephacetrile.
Laboratories, Horsham, Sussex serum
Cephaloridine
Eight male and one female volunteers gentamicin (’Genticin’, Nicholas) in
V. B. WHITMARSH
The
two females, all of whom had normal renal function (creatinine clearance > 100 ml. per minute), received 1 g. cephacetrile dissolved in 2’5 ml. of 2% lignocaine. All injections were given by one person. The drug was injected into either the anterolateral aspect of the thigh or the upper outer -quadrant of the buttock. At least 48 hours later the other site was used. The physical activity of the subject was made similar for each occasion. Blood-samples were taken just before a dose and 15, 30, 45, 60, 240, 360, and 480 minutes afterwards. Urine was collected before the dose and then 0-2, 2-4, 4-6, and 6-12 hours after the drug.
mg.
D. S. REEVES M. J. BYWATER R. WISE* Department of Medical Microbiology, Southmead Hospital, Bristol BS10 5NB
Summary
Cephacetrile Ten volunteers, eight males and
Gentamicin
AVAILABILITY OF THREE ANTIBIOTICS AFTER INTRAMUSCULAR INJECTION INTO THIGH AND BUTTOCK
Ciba
METHODS
supported by grants from the Swedish
National Association against Heart and Chest Diseases, Magnus Bergvalls Stiftelse, and the Swedish Medical Research Council
the
new
(’Celospor’,
Microbiology, Dudley Road
SERUM-LEVELS ((g./ml.) AND URINE EXCRETION (mg.) AFTER INJECTION INTO THIGH OR BUTTOCK OF 1 g. CEPHACETRILE, 500
mg. CEPHALORIDINE,
OR
80 mg.
GENTAMICIN ,
1422
_
_
_
-
Hours
Fig. 1-Mean
serum
levels of cephacetrile after into thigh or buttock.
injection of 1
g.
RESULTS
Cephacetrile Both the mean serum peak levels of the drug and the time at which the peak occurred differed with the site of the injection (table, fig. 1). After thigh injection, the mean peak serum level was 3 3’3 /.g. per ml. at 30 minutes and was 24 % higher than that after buttock injection (28’5 Mg. per ml. at 45 minutes). The differences at 15 and 30 minutes (Wilcoxon signed-rank test and Student’s t test) are statistically After 2 hours the mean serum significant (p<0’05). levels after buttock injection were higher than those after thigh injection, being significantly so at 8 hours (n<0°Ol). Analysis of urinary elimination of the drug showed a significantly greater excretion in the first 6 hours after injection in the thigh (table).
Cephaloridine There were no consistent differences in cephaloridine serum levels with regard to sites of injection. Our values for serum levels were analysed mathematically by Glaxo Laboratories using a curve-fitting computer program. The results obtained resembled those without this aid, but the computer data were used in the analysis for differences between sites of injection. The mean peak serum concentration after thigh injection was 16-9 ju-g. per ml. (range 14-1-23-9) at a mean time of 46-3 minutes. The corresponding figures after buttock injection were 15’7 ttg. per ml. (range 12-3203) at 43-3 minutes. The initial absorption-rates (1-19 and 1-25 jug. per ml. per minute) and ultimate half-lives (76-8 and 81-0 minutes) were similar for the thigh and buttock injections, respectively. There was, however, a striking difference in urine excretion over the time studied (table), there being significantly more cephaloridine excreted in the urine after thigh injection than after buttock injection. Gentamicin After injection the mean peak serum-levels occurred at 30 minutes with both intramuscular sites. Although the levels at this time (table) were higher after thigh injection than buttock injection, the differences were not significantly different. The mean serum
Fig. 2-Mean serum levels of gentamicin after injection of 80 mg. into thigh or buttock.
levels of the nine volunteers are shown in fig. 2. There were no significant differences in urinary excretion over the first 6 hours after injection (table). DISCUSSION
There seem to have been remarkably few systematic investigations into the influence of intramuscular injection site on drug pharmacology apart from that of Nora et all who described a more rapid effect of insulin injected intramuscularly into the deltoid region than the thigh. So far the buttock and thigh sites have been considered synonymous. In the wards, the site is almost always determined by nursing considerations rather than by medical prescriptions, and is all too rarely defined in pharmacological studies. We do not claim that the differences described are clinically significant, but the results do indicate a lack of synonymity between the two sites that could affect the clinical performance of other drugs. The difference between the drugs investigated could be accounted for by their formulations or physical properties, since such factors as volume and concentration of injection,2osmolarity, pH,3 and additives Exercan affect absorption in animal experiments. cise plays an important role in drug absorption,1-.fi and our findings may not apply to patients in bed. Illnesses may also affect the rate of absorption,7-9 as may local conditions at site of injection." These factors require further evaluation. We thank Glaxo Laboratories Ltd. and Nicholas Laboratories Ltd. for their support. Requests for reprints should be addressed to R. W. REFERENCES
Nora, J. J., Smith, W. D., Cameron, J. R. J. Pediat. 1964, 64, 547. Sund, R. B., Schon, J. Acta pharmac. toxic. 1964, 21, 213. Cutts, J. H., Walker, I. G. Cancer Res. 1966, 26, 1386. Ballard, B. E. J. pharm. Sci. 1966, 55, 515. Barnes, J. M., Trueta, J. Lancet, 1941, i, 623. Schmidt, H., Roholt, K. Acta path. microbiol. stand. 1966, 68, 396. Bauer, F. K., Cassen, B., Youtcheff, E., Shoop, L. Am. J. med. Sct. 1953, 255, 374. 8. De Groot, L. J., Pretell, E., Garcia, M. E. New Engl. J. Med. 1966 274, 133. 9. Irons, E. M. J. Am. med. Ass. 1950, 142, 97. 10. Winters, R. E., Litwack, K. D., Hewitt, W. L. J. infect. Dis. 1971. 124, suppl. p. 90. 1. 2. 3. 4. 5. 6. 7.