Vol. 15, No. 5
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1979, p. 658-661 0066-4804/79/05-68/04$02.00/0$02.00/0
Relationship Between Serum and Saliva Chloramphenicol Concentrations JEFFREY R. KOUP,t* ALAN H. LAU,' BARBARA BRODSKY,2 AND RICHARD L. SLAUGHTER'
Departments of Pharrnaceutics2 and Pharmacy,' State University of New York at Buffalo, Buffalo, New York 14214
Received for publication 7 February 1979
The relationship between serum and saliva chloramphenicol (CAP) concentrations was evaluated in 27 paired specimens collected from 20 hospitalized patients during therapy with the drug.
A
significant (R
-
0.80, P
* . 0
0
0
*
0 0 0
S6 0
5 SERUM
10-
CHLORAMPHENICOL
_
20
25
3
MCG/ ML
FIG. 1. Relationship between saliva and serum chloramphenicol concentrations in patients. The regression line (Y = 0.342 *X- 0.296) and correlation coefficient (R = 0.80) are shown.
groups, based upon serum concentration, and compared the saliva/serum concentration ratios that occurred in both groups. Since the distribution of these ratios was not nornal, the nonparametric Wilcoxon rank sum test was used to compare groups. No significant differences (P
Ratio: saliva/total serum concn.
0.28 0.43 0 0.27 0 0.10 0.18 0.45 0 0.56 0.19 0.47 0.18 0.17 0.37 0.35 0 0.45 0.40 0.37 0 0 0.28 0.92 0 0.37 0 0.25 0.23
> 0.05) existed between groups when samples with serum CAP concentrations greater than or equal to 5 ,ug/ml (N = 21) were compared to samples less than this value (N = 6) or when samples greater than or equal to 9.0 pLg/ml (N = 13) were compared to samples below this value (N = 14). Thus it would appear that factors other than poor assay sensitivity were responsible for variability in the saliva/serum concentration ratios. One potential cause ofthe observed variability could have been the marked variation in saliva flows observed in our patients. This problem partially reflects the poor clinical condition of our study patients. Since CAP is lipophilic, it may well undergo reabsorption in the salivary ducts after secretion. This process may produce a flow dependency in the saliva-to-serum concentration ratio. Unfortunately, precise flow data were not recorded on an individual basis, and this factor could not be further evaluated. Last, as has been previously mentioned, evalu-
CHLORAMPHENICOL IN SERUM AND SALIVA
VOL. 15, 1979
ation of saliva-to-serum drug concentration relationships in sick, hospitalized patients (11) has demonstrated significantly increased variability when compared to similar studies conducted in nornal volunteers (13) or ambulatory patients (7). Similar problems may have existed in our study population. An attempt was made to compare our results with those obtained by Bender et al. (2). Their serum and saliva concentration data obtained at 1 and 2 h postdose were chosen for comparison (N = 31). The serum concentrations obtained in these specimens were similar to those obtained in our study (mean, 9.6; standard deviation, 4.21). Their saliva/serum concentration ratio data demonstrated marked interpatient variability (mean ratio, 0.14; range, 0.0 to 0.45). Comparison of our ratio data with those of Bender et al. using the Wilcoxon rank sum test revealed no significant differences (P > 0.10). The dependence of the correlation between serum and saliva CAP concentrations on the two high serum CAP concentration values (30.5 and 31.3) seen in Fig. 1 was also evaluated. When these data were omitted, the degree of correlation decreased (R = 0.41) but remained significant (P < 0.05). In conclusion, it would appear that under the conditions of the present study serum and saliva CAP concentrations are significantly but variably related, and that differences in the binding of CAP to serum proteins does not account for the variability of this relationship. Furthermore, it would appear that, whereas a statistically significant correlation between serum and saliva CAP concentrations exists, the variability observed precludes reliance upon saliva CAP concentration as a guide to therapy. ACKNOWLEDGEMENT This work was supported in part by Public Health Service grant no. GM-20852 from the National Institute of General Medical Sciences.
LITERATURE CITED 1. Barkin, R. M., C. C. Greer, C. J. Schumacher, and K. McIntosh. 1976. Haemophilus influenzae meningitis. Am. J. Dis. Child. 130:1318-1321. 2. Bender, L. B., R. S. Pressman, and S. G. Tashman. 1953. Studies on excretion of antibiotics in human saliva. II. Chloramphenicol. J. Dent. Res. 32:287-293. 3. Burns, L. E., J. E. Hodgman, and B. Cass. 1959. Fatal circulatory collapse in premature infants receiving chloramphenicol. N. Engl. J. Med. 261:1318-1321. 4. Cook, C. E., E. Amerson, W. K. Poole, P. Lesser, and L. O'Tuama. 1976. Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay. Clin. Pharmacol. Ther. 18:742-747. 5. Craft, A. W., J. T. Brocklebank, E. N. Hey, and R. H.
661
Jackson. 1974. The "grey toddler" chloramphenicol toxicity. Arch. Dis. Child. 49:235-237. 6. Danhof, M., and D. D. Breimer. 1978. Therapeutic drug monitoring in saliva. Clin. Pharmacokin. 3:39-57. 7. Eney, R. D., and E. 0. Goldstein. 1976. Compliance of chronic asthmatics with oral administration of theophylline as measured by serum and salivary levels. Pediatrics 57:513-517. 8. Finegold, S. M. 1977. Therapy for infections due to anaerobic bacteria: an overview. J. Infect. Dis. 135(Suppl.):S25-S29. 9. Grafnetterova, J., Z. Vodrazka, D. Jandova, 0. Schuck, R. Tomasek, and J. Lachmanova. 1976. The binding of chloramphenicol to serum proteins in patients with chronic renal insufficiency. Clin. Neph. 6: 448-450. 10. Hendeles, L., S. Burkey, L. Bighley, and R. Richardson. 1977. Unpredictability of theophylline saliva measurements in chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 60:335-338. 11. Horning, M. G., L Brown, J. Nowlin, K. Lertratanangkoon, P. Kellaway, and T. E. Zion. 1977. Use of saliva in therapeutic drug monitoring. Clin. Chem. 23: 157-164. 12. Koup, J. R., B. Brodsky, A. H. Lau, and T. R. Beam. 1978. High-performance liquid chromatographic assay of chloramphenicol in serum. Antimicrob. Agents Chemother. 14:439-443. 13. Koysooko, R., E. F. Ellis, and G. Levy. 1974. Relationship between theophylline concentration in plasma and saliva of man. Clin. Pharmacol. Ther. 15:454-460. 14. Levine, P. H., W. Regelson, and J. F. Holiand. 1970. Chloramphenicol associated encephalopathy. Clin. Pharmacol. Ther. 11:194-199. 15. Lischner, H., S. J. Seligman, A. Kramer, and A. H. Parmelee. 1961. An outbreak ofneonatal deaths among term infants associated with administration of chloramphenicol. J. Pediatr. 59:21-34. 16. Mandel, L. D. 1974. Relation of saliva and plaque to caries. J. Dent. Res. 53:246-266. 17. McCurdy, P. R. 1963. Plasma concentration of chloramphenicol and bone marrow suppression. Blood 21:363372. 18. Sawchuk, R. J., and D. E. Zaske. 1976. Pharmacokinetics of dosing regimen which utilize multiple intravenous infusions: gentamicin in burn patients. J. Pharmacokinet. Biopharm. 4:183-195. 19. Scott, J. L., S. M. Finegold, G. A. Belkin, and J. S. Lawrence. 1965. A controlled double-blind study of hematologic toxicity of chloramphenicol. N. Engl. J. Med. 272:1137-1142. 20. Smick, K. M., P. K. Condit, R. L. Proctor, and V. Sutcher. 1964. Fatal aplastic anemia. An epidemiological study of its relationship to the drug chloramphenicol. J. Chronic Dis. 17:899-914. 21. Sutherland, J. M. 1959. Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. A. M. A. Dis. Child. 97:761-767. 22. Thompson, W. L., S. E. Anderson, J. J. Lipsky, and P. S. Lietman. 1975. Overdoses of chloramphenicol. J. Am. Med. Assoc. 234:149-150. 23. Weiss, C. F., A. J. Glazko, and J. K. Weston. 1960. Chloramphenicol in the newborn infant, a physiologic explanation of its toxicity when given in excessive doses. N. Engl. J. Med. 262:787-794. 24. Yunis, A. A. 1973. Chloramphenicol toxicity, p. 107-126. In R. H. Girdwood (ed.), Blood disorders due to drugs and other agents. Exerpta Medica, Amsterdam, Netherlands.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1979, p. 658-661 0066-4804/79/05-68/04$02.00/0$02.00/0
Relationship Between Serum and Saliva Chloramphenicol Concentrations JEFFREY R. KOUP,t* ALAN H. LAU,' BARBARA BRODSKY,2 AND RICHARD L. SLAUGHTER'
Departments of Pharrnaceutics2 and Pharmacy,' State University of New York at Buffalo, Buffalo, New York 14214
Received for publication 7 February 1979
The relationship between serum and saliva chloramphenicol (CAP) concentrations was evaluated in 27 paired specimens collected from 20 hospitalized patients during therapy with the drug.
A
significant (R
-
0.80, P
* . 0
0
0
*
0 0 0
S6 0
5 SERUM
10-
CHLORAMPHENICOL
_
20
25
3
MCG/ ML
FIG. 1. Relationship between saliva and serum chloramphenicol concentrations in patients. The regression line (Y = 0.342 *X- 0.296) and correlation coefficient (R = 0.80) are shown.
groups, based upon serum concentration, and compared the saliva/serum concentration ratios that occurred in both groups. Since the distribution of these ratios was not nornal, the nonparametric Wilcoxon rank sum test was used to compare groups. No significant differences (P
Ratio: saliva/total serum concn.
0.28 0.43 0 0.27 0 0.10 0.18 0.45 0 0.56 0.19 0.47 0.18 0.17 0.37 0.35 0 0.45 0.40 0.37 0 0 0.28 0.92 0 0.37 0 0.25 0.23
> 0.05) existed between groups when samples with serum CAP concentrations greater than or equal to 5 ,ug/ml (N = 21) were compared to samples less than this value (N = 6) or when samples greater than or equal to 9.0 pLg/ml (N = 13) were compared to samples below this value (N = 14). Thus it would appear that factors other than poor assay sensitivity were responsible for variability in the saliva/serum concentration ratios. One potential cause ofthe observed variability could have been the marked variation in saliva flows observed in our patients. This problem partially reflects the poor clinical condition of our study patients. Since CAP is lipophilic, it may well undergo reabsorption in the salivary ducts after secretion. This process may produce a flow dependency in the saliva-to-serum concentration ratio. Unfortunately, precise flow data were not recorded on an individual basis, and this factor could not be further evaluated. Last, as has been previously mentioned, evalu-
CHLORAMPHENICOL IN SERUM AND SALIVA
VOL. 15, 1979
ation of saliva-to-serum drug concentration relationships in sick, hospitalized patients (11) has demonstrated significantly increased variability when compared to similar studies conducted in nornal volunteers (13) or ambulatory patients (7). Similar problems may have existed in our study population. An attempt was made to compare our results with those obtained by Bender et al. (2). Their serum and saliva concentration data obtained at 1 and 2 h postdose were chosen for comparison (N = 31). The serum concentrations obtained in these specimens were similar to those obtained in our study (mean, 9.6; standard deviation, 4.21). Their saliva/serum concentration ratio data demonstrated marked interpatient variability (mean ratio, 0.14; range, 0.0 to 0.45). Comparison of our ratio data with those of Bender et al. using the Wilcoxon rank sum test revealed no significant differences (P > 0.10). The dependence of the correlation between serum and saliva CAP concentrations on the two high serum CAP concentration values (30.5 and 31.3) seen in Fig. 1 was also evaluated. When these data were omitted, the degree of correlation decreased (R = 0.41) but remained significant (P < 0.05). In conclusion, it would appear that under the conditions of the present study serum and saliva CAP concentrations are significantly but variably related, and that differences in the binding of CAP to serum proteins does not account for the variability of this relationship. Furthermore, it would appear that, whereas a statistically significant correlation between serum and saliva CAP concentrations exists, the variability observed precludes reliance upon saliva CAP concentration as a guide to therapy. ACKNOWLEDGEMENT This work was supported in part by Public Health Service grant no. GM-20852 from the National Institute of General Medical Sciences.
LITERATURE CITED 1. Barkin, R. M., C. C. Greer, C. J. Schumacher, and K. McIntosh. 1976. Haemophilus influenzae meningitis. Am. J. Dis. Child. 130:1318-1321. 2. Bender, L. B., R. S. Pressman, and S. G. Tashman. 1953. Studies on excretion of antibiotics in human saliva. II. Chloramphenicol. J. Dent. Res. 32:287-293. 3. Burns, L. E., J. E. Hodgman, and B. Cass. 1959. Fatal circulatory collapse in premature infants receiving chloramphenicol. N. Engl. J. Med. 261:1318-1321. 4. Cook, C. E., E. Amerson, W. K. Poole, P. Lesser, and L. O'Tuama. 1976. Phenytoin and phenobarbital concentrations in saliva and plasma measured by radioimmunoassay. Clin. Pharmacol. Ther. 18:742-747. 5. Craft, A. W., J. T. Brocklebank, E. N. Hey, and R. H.
661
Jackson. 1974. The "grey toddler" chloramphenicol toxicity. Arch. Dis. Child. 49:235-237. 6. Danhof, M., and D. D. Breimer. 1978. Therapeutic drug monitoring in saliva. Clin. Pharmacokin. 3:39-57. 7. Eney, R. D., and E. 0. Goldstein. 1976. Compliance of chronic asthmatics with oral administration of theophylline as measured by serum and salivary levels. Pediatrics 57:513-517. 8. Finegold, S. M. 1977. Therapy for infections due to anaerobic bacteria: an overview. J. Infect. Dis. 135(Suppl.):S25-S29. 9. Grafnetterova, J., Z. Vodrazka, D. Jandova, 0. Schuck, R. Tomasek, and J. Lachmanova. 1976. The binding of chloramphenicol to serum proteins in patients with chronic renal insufficiency. Clin. Neph. 6: 448-450. 10. Hendeles, L., S. Burkey, L. Bighley, and R. Richardson. 1977. Unpredictability of theophylline saliva measurements in chronic obstructive pulmonary disease. J. Allergy Clin. Immunol. 60:335-338. 11. Horning, M. G., L Brown, J. Nowlin, K. Lertratanangkoon, P. Kellaway, and T. E. Zion. 1977. Use of saliva in therapeutic drug monitoring. Clin. Chem. 23: 157-164. 12. Koup, J. R., B. Brodsky, A. H. Lau, and T. R. Beam. 1978. High-performance liquid chromatographic assay of chloramphenicol in serum. Antimicrob. Agents Chemother. 14:439-443. 13. Koysooko, R., E. F. Ellis, and G. Levy. 1974. Relationship between theophylline concentration in plasma and saliva of man. Clin. Pharmacol. Ther. 15:454-460. 14. Levine, P. H., W. Regelson, and J. F. Holiand. 1970. Chloramphenicol associated encephalopathy. Clin. Pharmacol. Ther. 11:194-199. 15. Lischner, H., S. J. Seligman, A. Kramer, and A. H. Parmelee. 1961. An outbreak ofneonatal deaths among term infants associated with administration of chloramphenicol. J. Pediatr. 59:21-34. 16. Mandel, L. D. 1974. Relation of saliva and plaque to caries. J. Dent. Res. 53:246-266. 17. McCurdy, P. R. 1963. Plasma concentration of chloramphenicol and bone marrow suppression. Blood 21:363372. 18. Sawchuk, R. J., and D. E. Zaske. 1976. Pharmacokinetics of dosing regimen which utilize multiple intravenous infusions: gentamicin in burn patients. J. Pharmacokinet. Biopharm. 4:183-195. 19. Scott, J. L., S. M. Finegold, G. A. Belkin, and J. S. Lawrence. 1965. A controlled double-blind study of hematologic toxicity of chloramphenicol. N. Engl. J. Med. 272:1137-1142. 20. Smick, K. M., P. K. Condit, R. L. Proctor, and V. Sutcher. 1964. Fatal aplastic anemia. An epidemiological study of its relationship to the drug chloramphenicol. J. Chronic Dis. 17:899-914. 21. Sutherland, J. M. 1959. Fatal cardiovascular collapse of infants receiving large amounts of chloramphenicol. A. M. A. Dis. Child. 97:761-767. 22. Thompson, W. L., S. E. Anderson, J. J. Lipsky, and P. S. Lietman. 1975. Overdoses of chloramphenicol. J. Am. Med. Assoc. 234:149-150. 23. Weiss, C. F., A. J. Glazko, and J. K. Weston. 1960. Chloramphenicol in the newborn infant, a physiologic explanation of its toxicity when given in excessive doses. N. Engl. J. Med. 262:787-794. 24. Yunis, A. A. 1973. Chloramphenicol toxicity, p. 107-126. In R. H. Girdwood (ed.), Blood disorders due to drugs and other agents. Exerpta Medica, Amsterdam, Netherlands.
