508
Br. J. clin. Pharmac.
LETTERS TO THE EDITORS
(I 979), 8
ABERRANTLY HIGH PHENYTOIN CONCENTRATIONS IN SALIVA. PRECAUTION IN MONITORING PHENYTOIN CONCENTRATIONS IN WHOLE SALIVA There have been many recent publications which have suggested that whole (mixed) saliva may be substituted for serum in monitoring phenytoin (DPH) therapy (Cook, Amerson, Poole, Lesser & O'Tuama, 1976; Homing, Brown, Nowlin, Lertratanangkoon, Kellaway & Zion, 1977; McAuliffe, Sherwin, Leppik, Fayle & Pippenger, 1977; Mucklow, Bending, Kahn & Dollery, 1978; Reynolds, Ziroyanis, Jones & Smith, 1976). In our previous studies of DPH concentrations in whole saliva specimens from both healthy volunteers and adult epileptics, we found no examples of abnormally high salivary DPH concentrations (Paxton, Rowell, Ratcliffe, Lambie, Nanda, Melville & Johnson, 1977; Paxton, Whiting & Stephen, 1977). In these studies and in several unpublished studies the % ratio of whole saliva to total serum concentration has ranged from 5-18% with a mean of 10%. The form of phenytoin used was phenytoin sodium in capsules (Dilantin, Parke Davis & Co.). However, in a recent study to investigate the salivary DPH concentrations throughout the day in epileptic children receiving twice daily doses of DPH, aberrantly high concentrations were occasionally found up to 3 h after DPH administration (Figure 1). All subjects studied were specifically receiving capsules and not tablets, as previous reports have shown that tablet forms of such drugs as digoxin, aspirin and carbamazepine leave remnants in the mouth, resulting in abnormally high 4
60mg
60mg
i
salivary concentrations when specimens are collected shortly after oral drug administration (Chiou, Chang & Peng, 1976; Joubert, Miller & Aucamp, 1976; Wada, Troupin, Friel, Remick, Leal & Pearmain, 1978). It was thought that this problem would be eliminated by the use of gelatin capsules. On account of these results, we investigated the DPH concentrations in whole saliva in two healthy
volunteers who retained a normal DPH oral dose (2 x 100 mg) in the mouth for 30-45 s and then expelled the dose. Both DPH capsules (100 mg, Parke Davis & Co. N.Z.) and sugar-coated tablets (100 mg Kempthorne Prosser & Co. N.Z.), were investigated. The results are shown in Figure 2. The greatest DPH concentration (8.8 jmol/l) was found in subject A, 5 min after retention of DPH capsules in the mouth for 45 s. In subject B, who retained the capsules for only 30 s, a maximum concentration of 3.8 ,umol/l was found 5 min after spitting out the capsules. Thereafter, concentrations declined to negligible levels (< 0.25 ,umol/l) after 1 h in subject A and 3 h in subject B. Lesser but still significant concentrations of DPH were also found in whole saliva after retention of the sugar-coated DPH tablets in the mouth for 45 s in both subjects. By 1-1.5 h these concentrations had fallen to negligible levels. These experiments were repeated by both subjects who, after having expelled the DPH dose, rinsed out 60mg
60mg
-3
E 1r2 a0 A
I6
c
1
I
08.00
12.00 Day 1
16.00
I -.1 20.00 08.00
12.00 16.00 Days 2 and 7
20.00
Time (h) Figure 1 Salivary DPH concentrations during two consecutive days, 1 and 2 (0) and day 7 (0) in a young epileptic patient receiving maintenance therapy of 2 x 30 mg DPH capsules twice daily. Each point is the mean of three analyses with the bars representing one standard deviation. Day 3, morning premedication saliva and serum samples gave DPH concentrations of 0.96 and 8.78 pmol/l respectively, resulting in a saliva to serum concentration ratio of 10.9%.
Br. J. clin. Pharmac. (1979), 8
LETTERS TO THE EDITORS
9
J.W. PAXTON & SUE FOOTE
8
Department of Pharmacology & Clinical Pharmacology, University of Auckland, School of Medicine, Auckland, New Zealand
7 0
E
509
6
Received June 5, 1979
5 I 0-
o
4
References
3
CHIOU, W.L., CHANG, K. & PENG, G.W. (1976). Precaution in the monitoring of drug levels in saliva. Abnormal salicylate levels after oral dosing. J. clin. Pharmac., 16, 158-160.
(I)
COOK, C.E., AMERSON, E., POOLE, W.K., LESSER, P. &
2~~~~~~~~
2
1
O'TUAMA, L. (1976). Phenytoin and Phenobarbital concentrations in saliva and plasma measured by radioimmunoassay. Clin. Pharmac. Ther., 18, 742-747.
3
Time (h)
Figure 2 Salivary DPH concentrations in subject A after retaining in the mouth for 45s 2xlOOmg capsules (0) and 2xlOOmg tablets (O) and in subject B, 2xlOOmg capsules for 30s (0) and 2 x 100 mg tablets for 45 s (E), and in subjects A (A) and B (A) after two mouth washes with water. Each point is the mean of duplicate analyses.
their mouths with two washes of water. In the subsequent saliva specimens no concentrations greater than 0.1 gmol/1 were detected. These results indicate that after oral dosing with both tablets and capsules of DPH a significant residue of drug may be left in the mouth which can contaminate the subsequent whole saliva specimens collected up to 3 h after administration. This problem may be eliminated by thorough cleansing of the mouth with water. We would recommend this procedure if whole saliva samples are to be obtained for DPH measurement during the 3 h period after administration of either capsules or tablets. This work was supported by grants from the M.R.C. (N.Z.) and from the National Children's Health Research Foundation (N.Z.).
NOWLIN, J., M.G., BROWN, L., HORNING, LERTRATANANGKOON, K., KELLAWAY, P. & ZION,
T.E. (1977). Use of saliva in therapeutic drug monitoring. Clin. Chem., 23, 157-164. JOUBERT, P.H., MOLLER, F.O. & AUCAMP, B.N. (1976). Salivary digoxin concentrations. Br. J. clin. Pharmac., 3, 673-674. McAULIFFE, J.J., SHERWIN, A.L., LEPPIK, I.E., FAYLE, S.A.
& PIPPENGER, C.E. (1977). Salivary levels of anticonvulsants: A practical approach to drug monitoring. Neurology, 27, 409-413. MUCKLOW, J.C., BENDING, M.R., KAHN, G.C. & DOLLERY, T. (1978). Drug concentration in saliva. Clin.
Pharmac. Ther., 24, 563-570. PAXTON, J.W., ROWELL, FJ., RATCLIFFE, J.G., LAMBIE, D.G., NANDA, R., MELVILLE, I.D. & JOHNSON, R..
(1977). Salivary phenytoin radioimmunoassay: A simple method for the assessment of non-protein bound drug concentrations. Eur. J. clin. Pharmac., 11, 71-74. PAXTON, J.W., WHITING, B. & STEPHEN, K.W. (1977). Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay. Br. J. clin. Pharmac., 4, 185-191. REYNOLDS, F., ZIROYANIS, P.N., JONES, N.F. & SMITH,
S.E. (1976). Salivary phenytoin concentrations in epilepsy and in chronic renal failure. Lancet, ii, 384-386. WADA, J.A., TROUPIN, A.S., FRIEL, P., REMICK, R., LEAL,
K. & PEARMAIN, J. (1978). Pharmacokinetic comparison of tablet and suspension dosage forms of carbamazepine. Epilepsia, 19, 251-255.
PHENYTOIN ABSORPTION IN PATIENTS WITH ILEOJEJUNAL BYPASS We read with interest the paper by Kennedy & Wade (1979) on phenytoin absorption in patients with ileojejunal bypass. In the discussion the authors express their
astonishment at finding a significantly shorter halflife of elimination in the bypass patients compared with the control group. Recalculation of the difference between the two means using the values
Br. J. clin. Pharmac.
LETTERS TO THE EDITORS
(I 979), 8
ABERRANTLY HIGH PHENYTOIN CONCENTRATIONS IN SALIVA. PRECAUTION IN MONITORING PHENYTOIN CONCENTRATIONS IN WHOLE SALIVA There have been many recent publications which have suggested that whole (mixed) saliva may be substituted for serum in monitoring phenytoin (DPH) therapy (Cook, Amerson, Poole, Lesser & O'Tuama, 1976; Homing, Brown, Nowlin, Lertratanangkoon, Kellaway & Zion, 1977; McAuliffe, Sherwin, Leppik, Fayle & Pippenger, 1977; Mucklow, Bending, Kahn & Dollery, 1978; Reynolds, Ziroyanis, Jones & Smith, 1976). In our previous studies of DPH concentrations in whole saliva specimens from both healthy volunteers and adult epileptics, we found no examples of abnormally high salivary DPH concentrations (Paxton, Rowell, Ratcliffe, Lambie, Nanda, Melville & Johnson, 1977; Paxton, Whiting & Stephen, 1977). In these studies and in several unpublished studies the % ratio of whole saliva to total serum concentration has ranged from 5-18% with a mean of 10%. The form of phenytoin used was phenytoin sodium in capsules (Dilantin, Parke Davis & Co.). However, in a recent study to investigate the salivary DPH concentrations throughout the day in epileptic children receiving twice daily doses of DPH, aberrantly high concentrations were occasionally found up to 3 h after DPH administration (Figure 1). All subjects studied were specifically receiving capsules and not tablets, as previous reports have shown that tablet forms of such drugs as digoxin, aspirin and carbamazepine leave remnants in the mouth, resulting in abnormally high 4
60mg
60mg
i
salivary concentrations when specimens are collected shortly after oral drug administration (Chiou, Chang & Peng, 1976; Joubert, Miller & Aucamp, 1976; Wada, Troupin, Friel, Remick, Leal & Pearmain, 1978). It was thought that this problem would be eliminated by the use of gelatin capsules. On account of these results, we investigated the DPH concentrations in whole saliva in two healthy
volunteers who retained a normal DPH oral dose (2 x 100 mg) in the mouth for 30-45 s and then expelled the dose. Both DPH capsules (100 mg, Parke Davis & Co. N.Z.) and sugar-coated tablets (100 mg Kempthorne Prosser & Co. N.Z.), were investigated. The results are shown in Figure 2. The greatest DPH concentration (8.8 jmol/l) was found in subject A, 5 min after retention of DPH capsules in the mouth for 45 s. In subject B, who retained the capsules for only 30 s, a maximum concentration of 3.8 ,umol/l was found 5 min after spitting out the capsules. Thereafter, concentrations declined to negligible levels (< 0.25 ,umol/l) after 1 h in subject A and 3 h in subject B. Lesser but still significant concentrations of DPH were also found in whole saliva after retention of the sugar-coated DPH tablets in the mouth for 45 s in both subjects. By 1-1.5 h these concentrations had fallen to negligible levels. These experiments were repeated by both subjects who, after having expelled the DPH dose, rinsed out 60mg
60mg
-3
E 1r2 a0 A
I6
c
1
I
08.00
12.00 Day 1
16.00
I -.1 20.00 08.00
12.00 16.00 Days 2 and 7
20.00
Time (h) Figure 1 Salivary DPH concentrations during two consecutive days, 1 and 2 (0) and day 7 (0) in a young epileptic patient receiving maintenance therapy of 2 x 30 mg DPH capsules twice daily. Each point is the mean of three analyses with the bars representing one standard deviation. Day 3, morning premedication saliva and serum samples gave DPH concentrations of 0.96 and 8.78 pmol/l respectively, resulting in a saliva to serum concentration ratio of 10.9%.
Br. J. clin. Pharmac. (1979), 8
LETTERS TO THE EDITORS
9
J.W. PAXTON & SUE FOOTE
8
Department of Pharmacology & Clinical Pharmacology, University of Auckland, School of Medicine, Auckland, New Zealand
7 0
E
509
6
Received June 5, 1979
5 I 0-
o
4
References
3
CHIOU, W.L., CHANG, K. & PENG, G.W. (1976). Precaution in the monitoring of drug levels in saliva. Abnormal salicylate levels after oral dosing. J. clin. Pharmac., 16, 158-160.
(I)
COOK, C.E., AMERSON, E., POOLE, W.K., LESSER, P. &
2~~~~~~~~
2
1
O'TUAMA, L. (1976). Phenytoin and Phenobarbital concentrations in saliva and plasma measured by radioimmunoassay. Clin. Pharmac. Ther., 18, 742-747.
3
Time (h)
Figure 2 Salivary DPH concentrations in subject A after retaining in the mouth for 45s 2xlOOmg capsules (0) and 2xlOOmg tablets (O) and in subject B, 2xlOOmg capsules for 30s (0) and 2 x 100 mg tablets for 45 s (E), and in subjects A (A) and B (A) after two mouth washes with water. Each point is the mean of duplicate analyses.
their mouths with two washes of water. In the subsequent saliva specimens no concentrations greater than 0.1 gmol/1 were detected. These results indicate that after oral dosing with both tablets and capsules of DPH a significant residue of drug may be left in the mouth which can contaminate the subsequent whole saliva specimens collected up to 3 h after administration. This problem may be eliminated by thorough cleansing of the mouth with water. We would recommend this procedure if whole saliva samples are to be obtained for DPH measurement during the 3 h period after administration of either capsules or tablets. This work was supported by grants from the M.R.C. (N.Z.) and from the National Children's Health Research Foundation (N.Z.).
NOWLIN, J., M.G., BROWN, L., HORNING, LERTRATANANGKOON, K., KELLAWAY, P. & ZION,
T.E. (1977). Use of saliva in therapeutic drug monitoring. Clin. Chem., 23, 157-164. JOUBERT, P.H., MOLLER, F.O. & AUCAMP, B.N. (1976). Salivary digoxin concentrations. Br. J. clin. Pharmac., 3, 673-674. McAULIFFE, J.J., SHERWIN, A.L., LEPPIK, I.E., FAYLE, S.A.
& PIPPENGER, C.E. (1977). Salivary levels of anticonvulsants: A practical approach to drug monitoring. Neurology, 27, 409-413. MUCKLOW, J.C., BENDING, M.R., KAHN, G.C. & DOLLERY, T. (1978). Drug concentration in saliva. Clin.
Pharmac. Ther., 24, 563-570. PAXTON, J.W., ROWELL, FJ., RATCLIFFE, J.G., LAMBIE, D.G., NANDA, R., MELVILLE, I.D. & JOHNSON, R..
(1977). Salivary phenytoin radioimmunoassay: A simple method for the assessment of non-protein bound drug concentrations. Eur. J. clin. Pharmac., 11, 71-74. PAXTON, J.W., WHITING, B. & STEPHEN, K.W. (1977). Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay. Br. J. clin. Pharmac., 4, 185-191. REYNOLDS, F., ZIROYANIS, P.N., JONES, N.F. & SMITH,
S.E. (1976). Salivary phenytoin concentrations in epilepsy and in chronic renal failure. Lancet, ii, 384-386. WADA, J.A., TROUPIN, A.S., FRIEL, P., REMICK, R., LEAL,
K. & PEARMAIN, J. (1978). Pharmacokinetic comparison of tablet and suspension dosage forms of carbamazepine. Epilepsia, 19, 251-255.
PHENYTOIN ABSORPTION IN PATIENTS WITH ILEOJEJUNAL BYPASS We read with interest the paper by Kennedy & Wade (1979) on phenytoin absorption in patients with ileojejunal bypass. In the discussion the authors express their
astonishment at finding a significantly shorter halflife of elimination in the bypass patients compared with the control group. Recalculation of the difference between the two means using the values
