MIXED SALIVARY LEVELS OF CLINDAMYCIN FOLLOWING SINGLE DOSE ORAL ADMINISTRATION

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1 British ~urnal f ral Surgery (1972), I, MIXED SALIVARY LEVELS F CLINDAMYCIN FLLWING SINGLE DSE RAL ADMINISTRATIN A. A. QUAYLE~ F.D.S.~ Ph.D. St Lawrence Hspital, Chepstw, Mn. and V. B. WrlITMARSH, M.B., B.S., L.R.C.P. Upjhn Ltd., Crawley, Sussex INTRDUCTIN I1~ salivary gland infectins it is usual fr the infective prcess t affect the duct system f the gland. If such an infectin is bacterial in rigin and it is decided t treat the cnditin with antibitics, it is imprtant t chse a drug which is nt nly effective against the bacteria invlved, but which als gains access t their immediate envirnment in therapeutically effective cncentratins. Thus, the antibitic f chice shuld be secreted r filtered int the saliva and nt merely be present in the bld and interstitial fluid within the gland. With these cnsideratins in mind, it was decided t determine the salivary levels f clindamycin (Dalacin C (g)) in a grup f vlunteer subjects, fllwing a single ral dse f the drug. This particular drug was chsen as it is knwn t be rapidly absrbed fllwing ral administratin (Wagner, 1968), and preliminary studies had shwn that salivary levels f the drug were measurable. Furthermre, shuld it reach the saliva it wuld be recycled repeatedly t the gastr-intestinal tract and thence t the bld again, rendering it available nce mre fr secretin int the saliva. In additin, absrptin is nt appreciably affected by the cn- Cmitant administratin f fd, and serum levels abve the minimum inhibitry cncentratin (M.I.C.) fr mst Gram-psitive rganisms are maintained fr at least 6 hurs (McGehee, 1968). METHDS Clinical Aspects f the Trial. Six healthy yung adult males, all dental undergraduates, were used fr the first part f these investigatins. The subjects had fasted vernight and had been asked t abstain frm alchl during the previus evening. Smking was nt permitted during the experiment. After a pre-dse sample f saliva had been cllected, each subject swallwed tw I5 mg capsules f clindamycin with abut 30 ml f water. Fr the next 6 hurs salivary samples were taken cntinuusly, the saliva being cllected in labelled bttles thrughut that perid except fr three pre-arranged breaks, each f I minutes duratin, when fd was taken. Fllwing the ingestin f fd, the muth was cleansed as thrughly as pssible with a muthwash f water. The first few muthfuls f saliva were swallwed fuwing this prcedure, t minimise the dilutin by the muthwash f the subsequent salivary sample. n anther ccasin during a similar experiment invlving tw subjects, bld samples were taken at intervals during the trial in additin t cntinuus 24

2 MIXED SALIVARY LEVELS F CLINDAMYCIN 2 5 salivary sampling, s that a cmparisn f serum and salivary levels f clindamycin culd be made. In a third experiment, six nrmal vlunteers received ne 15 mg capsule f clindamycin. A similar prtcl t that used in the previus studies was fllwed and saliva specimens were taken as befre. Bld fr serum levels f clindamycin were taken pre-dse, and at 5 and 255 minutes pst-dse. Micrbilgical Assay f Clindamyein in the Bld and Saliva Samples. Assays were carried ut by a well-plate diffusin methd using Penassay See Agar (Difc N. I) inculated with Sarcina lutea ATCC 934 I. Standard curves were prepared in pled serum fr the serum assays and in.i m phsphate buffer, ph 7, fr the saliva assays. The serum and saliva were applied t the plates undiluted. The plates were read after an I8-hur incubatin at 32 C. RESULTS The clindamycin assays fr the first tw experiments were sensitive dwn t a level f '25 mcg/ml and fr the third dwn t.2 mcg/ml. When the samples cntained traces f clindamycin as shwn by inhibitin znes smaller than culd be accurately measured, they were recrded as.25 r.2 mcg/ml and regarded as zer fr calculatin f the means. Full assay results fr the first experiment are given in Table I. Tables II TABLE I Experiment I Clindamycin assays n saliva samples cllected at intervals frm vlunteers wh received 30 mg clindamycin Assay mcg clindamycin/ml saliva Sample time mins. Subject Mean Pre-dse I I20 I I '5 I "62 2"10 I "45 1"15 I "03 0"78 0"64 0"56 '5 '4 0-3I 0"39 0"33 1"15 I'35 0"70 0' '26 0"31 0"29 < '54 0'I8 I "95 ' <0'25 < 0-25 <0'2 5 <0'25 <0'25 4 <525 <625 I " [ '66 [ 1"8 I'87 0'88 0"33 0"38 0"94 < 0,25 I "20 1"60 0"82 I'75 0"62 I "22 '49 0"74 0'48 I '08 0"4I I'03 '35 '85 '3-69 0"28 0"45 0"48 '39 0' "97 0" "42 0"54 0"28 0"27 'I 4 0"I8.I 3 'II

3 26 BRITISH JURNAL F RAL SURGERY TABLE n Experiment 2 Clindamycin assays n bld samples cllected at intervals frm vlunteers wh received 30 mg clindamycin Sample time mins. Assay mcg clindamycin/ml serum Subject I Subject 2 Mean Pre-dse I5 i8 2I " I'42 I "66 I'53 I "20 I "20 I "24 0"75 '58 0"52 < '25 2"15 I'58 0"98.8 I'9 I'I '93 0"98 0"47 0"64 0"58 0"54 'I 3 2"0 I'46 I "20 I'23 1"31 1"15 I'6 I'II '61 ' "53 TABLE III Experiment 2 Clindamycin assays carried ut n saliva samples cllected frm vlunteers wh received 3 mg clindamycin Sample time mins. Assay mcg clindamycin/ml saliva Subject 1 Subject 2 Mean Pre-dse I I2 13 I5 I8 2I " ' '35 0" < 0.25 < '25 '64 i.2 '65 ' "32 '41.3 I 0"55 0'94 0"58 0"46 0"38 0"36 0"35 '15 "13

4 MIXED SALIVARY LEVELS F CLINDAMYCIN 27 TABLE IV Experiment 3 Clindamycin assays carried ut n bld samples cllected frm vlunteers wh received 15 mg clindamycin Assay mcg clindamycin/rnl serum Subject Sample time mins. Mean A B C D E F Pre-dse I'I < 0.2 0"85 '2I " "70 I "05 I " TABLE V Experiment 3 Clindamycin assays carried ut n saliva samples cllected frm vlunteers wh received I5 mg clindamycin ea( Assay mcg clindamycin/ml saliva Subject Sample time mins. A B C D E F Pre-dse I '20 "21 0'22 0" "32 0'58 '26 0'23 '21 0"37 < '20 All assa 0'20 0'20 0" "24 0'25 rs '77 0"55 0"49 '6 0"2 3 0'85 '64 " "32 0' " "24 '19 0"04

5 28 BRITISH JURNAL F RAL SURGERY and III shw the results f the secnd experiment and Tables IV and V the results f experiment 3. The results f experiment 2 are als shwn in Figure I. The average serum levels are represented by the graphed line whilst the salivary levels are shwn by the shaded clumns. In this study the peak salivary level achieved was slightly less than that determined in the first study (i.45 mcg/ml), but there was gd agreement between the serum and salivary levels which was seen again in the third study. 2.0 Mean~Serum level [] Mean Salivary level []Meal Break 1.5 E _= '~ ~.0 0'~ I ~ ~ mg Time minutes Clindamycin FIG. i. 210 [] DISCUSSIN The results presented demnstrate that fllwing a single ral dse f I5 mg r 3 mg f clindamycin, the drug is present in the saliva in clinically useful cncentratins, and these exceed '25 mcg/ml fr a perid f several hurs. It is nt pssible t state, n the basis f the results, exactly hw clindamycin gains access t the saliva frm the interstitial fluid. Hwever, the results d shw that an increase f apprximately 45 per cent in the serum cncentratin f the drug results in a much greater increase in the salivary level (abut I per cent --cmpare experiments 2 and 3). This indicates that active transprt culd be partially respnsible fr the transfer f clindamycin frm interstitial fluid t saliva, since pure filtratin culd accunt fr at the mst a I : I rati between the serum and salivary level changes. It is pssible, f curse, that bth active transprt and passive filtratin are invlved. The clinical significance f these results is threefld. Firstly, since the drug gains access t the saliva in therapeutically significant cncentratins it

6 MIXED SALIVARY LEVELS F CLINDAMYCIN 2 9 may be particularly useful in the treatment f salivary gland infectins caused by clindamycin-susccptiblc rganisms. As stated in the intrductin t this paper, a drug will bc mre effective if it is present in the lumen f the salivary gland ductules, rather than being cnfined t the serum and interstitial fluid nly. In this cntext it is pcrtincnt t mentin a case f acute partitis treated by ne f the authrs (A. A. Q.) which respnded rapidly t treatment with clindamycin, fllwing unsuccessful treatment with tw types f penicillin, althugh the bacterilgical reprt indicated that the infecting rganism was susceptible t bth pcnicillins used. It shuld bc mentined, hwever, that there is n psitive evidence t indicate that the infected gland will secrete in the same manner as a healthy gland, and that n assay f salivary clindamycin was carried ut in this case. Nevertheless, it is als relevant t pint ut that ther wrkers have shwn that tw types f pcnicillins d nt gain access t saliva in ther than extremely lw cncentratins (Spicrs, Stcnhuse, Stephen and Wallace 1971). The secnd clinically relevant feature f the results described in this paper is that, fllwing rally administered clindamycin, susceptible bacteria causing r cntaminating an ral lesin will be subjected t bth hacmatgcnus and tpical expsure t the drug fr prlnged perids. In this cntext we wuld pint ut that the minimum bactericidal cncentratin (M.B.C.) f clindamycin is less than.i mcg/ml fr hacmlytic streptccci and pncumccci, and less than I- mcg/ml fr staphylccci. The crrespnding figure fr minimum inhibitry cncentratins are 0.04 mcg/ml and.i mcg/ml respectively (McGehcc, 1968). Finally, since this study has shwn that clindamycin is freely available in saliva during treatment, it rc-cmphasiscs the nccd t inspect the ral cavity during antibitic therapy, t bserve any clinical signs f knbalancc f the ral flra which may be caused by the presence f the drug in the saliva. This wrk is currently being extended, and it is hped in due curse t cmpare the results btained in similar experiments with a variety f antibitics. ~g ACKNWLEDGEMENTS The wrk presented in this paper was carried ut while ne f us (A. A. Q.) was a registrar in ral surgery at Waltn Hspital, Liverpl. The authrs wish t thank Mr H. A. Priestland and Mr I. Chippendale, cnsultant ral surgens at Waltn Hspital, fr their encuragement in relatin t this study, and Mrs G. A. Hssack fr perfrming the serum and saliva, assays. REFERENCES McGEHEE, R. F. (I968). American Jurnal f Medical Science, 256, 279. SPIERS, C. F., STENHUSE, D., STEPHEN, K. W. ~% WALLACE, E. T. (1971). Jurnal f Pharmaclgy, 43, 242. WAGNER, J. G. (1968). American Jurnal f Medicine, 256, 25. British