Oxytetracycline in Dogs

Transcription

1 ANIMIcRoAL AGvWs AND CHEMOTHERAPY, Dec. 1975, p Copyright C 1975 Americn Society for Microbiology Vol. 8, No. 6 Printed in U.S.A. Reltion Between Lipophilicity nd Phrmcologicl Behvior of Minocycline, Doxycycline, Tetrcycline, nd Oxytetrcycline in Dogs MICHAEL BARZA,* RICHARD B. BROWN, CAROLYN SHANKS, CHARLES GAMBLE, AND LOUIS WEINSTEIN Infectious Disese Service, Deprtment of Medicine nd Deprtment ofanesthesiology, Tufts-New Englnd Medicl Center Hospitl, Boston, Msschusetts Received for publiction 20 August 1975 Four tetrcyclines were studied in dogs to determine the reltion between their lipophilicity nd vrious other phrmcologicl chrcteristics. Lipid solubility correlted inversely with the men concentrtion of drug in rteril plsm nd renl uptke nd excretion, nd directly with the biliry concentrtion grdient (level in bile/level of free drug in serum). Only the more lipophilic congeners minocycline nd doxycycline pssed the blood-brin nd blood-oculr brriers in detectble concentrtions. Men levels of minocycline in the brin exceeded those of doxycycline by lmost threefold; the difference ws of borderline sttisticl significnce (P = 0.05 to 0.1). Lipophilicity correlted inversely with the concentrtion of ntibiotic in renl medull but not in renl cortex or in the liver. When intestinl loops contining sline, milk, or 10% Gelusil were studied, the only combintion exhibiting striking intrluminl ccumultion ws doxycycline in milk. These results indicte tht lipophilicity correltes with mny, but not ll, of the trnsport chrcteristics of tetrcycline ntibiotics. Since the discovery of the tetrcycline ntibiotics over 25 yers go, number of moleculr modifictions hve been mde with view to improving tissue distribution, prolonging their hlf-life, ugmenting intestinl bsorption, nd enhncing their ntibcteril ctivity. Mny of these objectives hve been met in minocycline nd doxycycline (6, 9, 10, 25, 26, 34, 41). Of dditionl interest is the fct tht neither of these tetrcyclines ppers to require mjor djustment in dose in the presence of renl filure (6, 41), suggesting tht they re extensively eliminted by nonrenl routes. Doxycycline hs been demonstrted to be excreted extensively vi the intestine (41). The dt reltive to minocycline, however, re inconclusive, nd biliry excretion (29), intestinl excretion (6), nd metbolic degrdtion (25) hve ll been considered s possible modes of nonrenl elimintion of this gent. Minocycline nd doxycycline re mrkedly more lipid soluble thn is tetrcycline or oxytetrcycline (Tble 1). The lipophilicity of minocycline is prticulrly striking nd ppers to endow this gent with high degree of intestinl bsorption nd tissue penetrtion. Although number of investigtors hve exmined the phrmcologicl behvior of vrious tetrcyclines in terms of their physicochemicl 713 properties, there hve been few comprisons of minocycline nd doxycycline in this respect. The purpose of the present investigtion ws to compre minocycline, doxycycline, tetrcycline, nd oxytetrcycline with regrd to their uptke nd excretion by the liver nd kidney, nd their penetrtion into ilel contents, brin, cerebrospinl, nd oculr fluids. The studies were crried out in cnine model tht hs been employed in previous investigtions in our lbortory (5). MATERIALS AND METHODS Surgicl preprtion. The surgicl preprtion procedure hs been described previously (5). Helthy mongrel dogs weighing 20 to 29 kg were nesthetized. Intrvsculr cnnuls were plced in the femorl rtery nd vein nd left renl, portl, nd heptic veins for spirtion of blood. Clotting ws prevented by flushing the cnnuls with heprin. Flow probes (Stthm Co., Los Angeles, Clif.) were pplied to the left renl nd portl veins. Men rteril pressure ws recorded with pressure trnsducer. Both ureters nd the common bile duct were ctheterized, nd the cystic duct ws ligted. Severl dditionl procedures not performed in previous studies of this model were crried out. The terminl ileum ws mobilized, nd three contiguous segments were ligted with hevy silk sutures. Cre ws tken to insure tht the blood supply

2 714 BARZA ET AL. TABLE 1. Some physicochemicl chrcteristics of four tetrcyclines Chloroform- Octnol-w- Drug wter prti- ter prtition Cheltion Drg tion coeffi- ofiin cient t ph peh7ien(8)t tb (35) cu 7.4 (36) p. 8 Minocycline b NKc Doxycycline Tetrcycline Oxytetrcycline Dt from personl communiction, R. G. Kelly, Lederle Lbortories. b Vlue for minocycline inferred from dt t other ph vlues. c NK, Not known. ws intct. A cnnul ws inserted into ech loop through purse-string suture, nd 60 ml of norml sline, milk, or 10% Gelusil (Wrner/Chilcott, Morris Plins, N. J.) in norml sline ws infused into the loops in rndom order. The contents of clcium, mgnesium, nd iron in the milk were 1.18, 0.12, nd mg/ml, respectively. The solution of 10% Gelusil contined no clcium, 2.6 mg of mgnesium, nd 1.5 mg of luminum per ml. When the surgicl preprtion ws complete, infusions of ntibiotics were strted. Antibiotic infusions. Ech of the following tetrcyclines ws given intrvenously to five dogs: minocycline hydrochloride, tetrcycline hydrochloride (Lederle Lbortories, Perl River, N.Y.), doxycycline hyclte, nd oxytetrcycline hydrochloride (Pfizer Lbortories, New York, N.Y.). A loding dose of 5 mg/kg ws given over 2 to 5 min. Minocycline, however, ws injected over 10 to 30 min becuse rpid dministrtion of this gent produced mrked hypotension. A continuous infusion of ntibiotic ws then given t the rte of 1 mg/kg per h with n infusion pump. The drugs were dissolved in norml sline in concentrtion such tht the hourly quntity ws contined in 72 ml. Collection of specimens. Blood ws obtined from the intrvsculr cnnuls t 15-min intervls. Flow rtes were mesured in the renl nd portl veins t the sme time. Urine nd bile were collected over 30-min periods, nd 1 ml of the contents of the ilel loops ws spirted every hlf hour. At the end of the 3-h period of infusion, wedge biopsies were obtined from the liver nd left kidney; the ltter ws dissected into cortex nd medull. A section of the wll of ech ilel loop ws lso excised. The queous humor of both eyes ws spirted through 25-guge needle, nd the vitreous ws obtined fter enucletion of the eye. Cerebrospinl fluid ws procured by cisternl puncture. Brin tissue ws obtined through burr hole in the prietl region of the skull. Specimens from the brin, spinl fluid, nd eye were generlly removed bloodlessly. All tissues nd fluids were frozen (-20 C) nd ssyed within 48 h. Vitl signs, cid-bse sttus, nd hemtocrit were mesured every 15 min nd showed no significnt ANTiMICROB. AGZNTS CHEMOTHIR. bnormlities, except for the trnsient hypotension observed with minocycline. Creful ttention ws pid to hemostsis throughout the studies. Assys. The techniques used were similr to those described elsewhere (5). Concentrtions of the drugs were determined by n gr-diffusion biossy employing Bcillus subtilis spores (ATCC 6633) nd ntibiotic medium no. 8 (Difco Lbortories, Detroit, Mich.). Tissues were homogenized in 2.5% solution of trypsin equl in volume to three times the weight of the tissue. Preliminry studies demonstrted tht stndrds dissolved in norml sline produced zones of inhibition of the sme size s those resulting from n identicl concentrtion of ntibiotics in trypsinized tissue homogentes. For this reson, tissues were ssyed using sline stndrds. Pooled cnine serum, bile, milk, nd 10% Gelusil were used to prepre stndrds for ssy of the corresponding specimens. Oculr queous nd vitreous humor nd spinl fluids were ssyed ginst stndrds diluted in sline. For ech of these tissues nd fluids, the ccurcy of the biossy ws + 15%. Studies using 51Cr-tgged cnine erythrocytes indicted tht the content of the blood in the biopsies of the liver, kidney, ileum, nd brin ws pproximtely 4%. All sttisticl nlyses were performed using n unpired t test. RESULTS Effects of loding dose on blood pressure. The men rteril blood presure ws not ffected by infusion of oxytetrcycline or tetrcycline. Injection of the initil dose of doxycycline over 2 to 5 min produced slight (11.4%) rise in men rteril pressure over bse-line vlues (P < 0.05). Infusion of minocycline t the sme rte resulted in severe hypotension; thus, loding doses of this gent were dministered over 10 to 30 min. Even t this slower rte, minocycline produced decline in men rteril blood pressure of 37% (stndrd error, 11%) compred with vlues before injection (P < 0.02). The effect, however, ws trnsient, with return to bse-line levels within 60 mn. Intrvsculr concentrtions of tetrcyclines. Levels of ntibiotic were highest during h 1 of infusion, reflecting the effect of the loding dose. Stble concentrtions were ttined within 60 to 90 min with ech gent. The men levels of drugs in rteril plsm during h 3 of infusion re shown in Tble 2. Although differences mong the four gents were smll, there ws n inverse reltion between lipid solubility (Tble 1) nd the levels of ntibiotics in rteril serum. Concentrtions of minocycline nd doxycycline in the heptic vein were lower thn those in the portl or renl veins (P < 0.01). In contrst, concentrtions ofoxytetrcycline were lower in the renl vein thn in the portl or heptic veins (P < 0.01).

3 VOL. 8, 1975 TABLE 2. Concentrtions of tetrcyclines in vrious vessels during h 3 of continuous infusion Concn (jag/ml) Vessel fminocyc- Doxycyc- Tetrcy- Oxytetrline line cline cycline Femorl rtery Portl vein 3.4 ± ± Heptic vein 2.8 ± ± ± Renl vein ± 0.4] Men nd stndrd error of four vlues obtined t 15- min intervls; ech drug ws dministered to five dogs. Percentge of extrction by liver nd kidney. The percentge of extrction vlue represents the percentge of ntibiotic removed from ech milliliter of plsm during pssge through the orgn; the method of clcultion hs been described previously (5). Stble vlues were reched during h 2 of infusion. The percent extrction for both the liver nd kidney during h 3 rnged from 5 to 18% for ll the drugs (Tble 3); there ws no cler reltion to lipid solubility (Tble 1). Absolute extrction by the liver nd kidney. The rte of uptke (bsolute extrction) of drug by ech orgn (microgrms per minute) ws clculted s the difference in concentrtion between efferent nd fferent vessels multiplied by the flow rte of plsm (5). The men renl plsm flow rtes during h 3 of infusion rnged from 70 to 90 ml/min for ll nimls, except those receiving minocycline (44 ml/min). Portl flow rtes rnged from 120 to 180 ml/min, except in dogs receiving doxycycline (237 ml/min). Vlues for bsolute renl extrction were stble by 2 h, wheres those for heptic extrction fluctuted throughout the study. During h 3 of infusion (Tble 3), extrction by the kidneys ws significntly higher for tetrcycline nd oxytetrcycline thn for the two more lipophilic gents (P < 0.01 in ech instnce). In contrst, no reltion to lipid solubility ws evident for heptic extrction. Excretion in urine nd bile. The concentrtions nd rtes of excretion in urine nd bile becme stble during h 2 (Fig. 1). The four congeners differed significntly from one nother with respect to their levels nd rtes of excretion in urine (P < 0.02 in ech instnce), nd both of these mesurements correlted inversely with their reltive lipophilicity (Tble 1). Most striking ws the low urinry concentrtion of minocycline (men, 3,ug/ml) during h 3. The ph of urine vried from 6.2 to 8.5. In contrst to the findings in urine, there were only minor disprities mong the ntibiotics in their biliry excretion. There were no LIPOPHILICITY AND PHARMACOLOGICAL BEHAVIOR significnt differences in either concentrtion or rte of excretion in bile mong the four gents during the first 2 h. By 3 h (Fig. 1), the biliry level of tetrcycline ws significntly lower thn tht of minocycline (P < 0.05), nd its rte of excretion ws less thn tht of doxycycline (P < 0.05). The ph of bile rnged from 7.0 to 7.6 (medin, 7.4) for ech tetrcycline. Concentrtions in vrious tissues nd fluids. The concentrtions of minocycline nd doxycycline were significntly higher thn those of either oxytetrcycline or tetrcycline in the cerebrospinl fluid, brin, nd oculr queous nd vitreous humor (P < 0.05 in ech instnce) (Fig. 2). The men levels of minocycline or docycycline in ll of these sites rnged from 0.7 to 2.9,ug/ml, wheres tetrcycline nd oxytetrcycline were undetectble (<0.3,ug/ml). The concentrtions of minocycline were similr to those of doxycycline, except in the brin where the difference ws of borderline sttisticl significnce (P = 0.05 to 0.1). Levels of oxytetrcycline in the liver were significntly higher thn those of tetrcycline (P < 0.05) or minocycline (P < 0.01). TABLE 3. Percentge of extrction nd bsolute extrction of tetrcyclines by the kidney nd liver during h 3 of infusion Antibiotic Absolute extrction Extrction (%) (iag/min) T Left kid- Liver Le kid- Liver ney ney x 2 Minocycline Doxycycline ± Tetrcycline 15 ± 2 5 ± ± ± 22 Oxytetrcycline 18 ± 1 10 ± ± _± 23 Men nd stndrd error of four vlues in ech dog; ech drug ws dministered to five nimls. T _ 0 Minocycline 0 Doycydine Tetrocycline cl ISO 6000o 0 Oxytelrcydline Urin Bile Urine Bil FIG. 1. Concentrtions nd rtes of excretion of ntibiotics in urine nd bile; men nd stndrd error of vlues during h 3 of infusion. Urinry concentrtions re from the left ureter; urinry excretion represents the sum of the vlues from both ureters.

4 716 BARZA ET AL. 23 O Crenbrospinl Brin Oculo*,, Oe IJ~~~~~~~~~~E)mimoeyd;ne DON) v@cyclin trcyclnr tetrcycline I~~~~~~~~~~~ c 50 Liver Renl Renl T 30 o20 I0 0 1 Cortex Medli Telit (Sline Loop) DUS Arteril Plsm FIG. 2. Concentrtions (men nd stndrd error) of ntibiotics t vrious sites fter 3 h of infusion. Note the difference in scle of the two grphs. Asterisks indicte loctions in which no ntibiotic could be detected (<0.3 pg/mi). Minocycline ws present in lower concentrtions thn the other three gents in renl cortex (P < 0.02). There ws n inverse correltion between lipophilicity nd the levels of drugs. in the renl medull; however, the only differences of sttisticl significnce in this tissue were between minocycline nd oxytetrcycline (P < 0.05). The concentrtion of the tetrcyclines in vrious tissues nd fluids ws clculted s concentrtion grdient, tht is, s percentge of the level of free drug in the serum (Tble 4). The ltter vlue ws derived by multiplying the concentrtion of drug in rteril serum (Tble 2) by the unbound frction, using the protein binding dt shown in Tble 5. The resultnt men levels of free ntibiotics were (microgrms per milliliter): minocycline, 1.02; doxycycline, 0.95; tetrcycline, 1.12; nd oxytetrcycline, Thus, the concentrtions of free drug were pproximtely fivefold s high for oxytetrcycline s for the other gents. For comprtive purposes, dt reported by other investigtors re lso shown in Tble 4. There ws no distinct reltion between lipophilicity nd the concentrtion grdient for renl or heptic tissue. In contrst, there ws direct correltion between lipid solubility nd the concentrtion grdient in bile, nd n inverse correltion in urine. The two more lipophilic gents exhibited much higher concentrtion grdients in the brin, cerebrospinl fluid, nd queous nd vitreous humor thn did tetrcycline nd oxytetrcycline. In no instnce were we ble to show strictly liner reltion between the lipid-wter prtition coefficient (Tble 1) or its logrithm nd the concentrtions or concentrtion grdients ofthe ntibiotics (36). ANTIMICROB. AGENTS CHEMOTHE. Concentrtion in wll nd contents of ilel loops. There were no significnt differences mong the ntibiotics with respect to their concentrtions in the wll of sline-contining loops (Fig. 2). The levels of ntibiotics in the wlls of loops contining milk or Gelusil were similr to those in segments filled with sline. The concentrtions of drugs in the contents of ilel loops showed progressive increse during the course of infusions (Tble 6). A striking ccumultion of doxycycline ws observed in segments contining milk; these exceeded the levels encountered with ny other combintion of ntibiotic nd type of ilel fluid (P < 0.05). DISCUSSION The trnsport of ntibiotics from serum into interstitil fluid nd tissues is influenced by number of fctors, including serum protein binding nd lipid solubility of the compound (16, 18). The cpillry bed of most tissues contins smll fenestrtions tht permit redy pssge of substnces of moleculr weight up to bout 1,000. Thus, tht portion of most ntibiotics not bound to protein penetrtes the interstitil fluid with reltive ese. In contrst, diffusion cross the blood-brin nd blood-oculr brriers, intestinl epithelium, nd cell membrnes depends upon movement through lipoid brrier. In generl, lipid solubility fcilittes trnsport in these circumstnces. These correltes, however, re reltive, nd the phrmcologicl behvior of the tetrcyclines is influenced mrkedly by their pk, degree of cheltion by metls, nd binding to other cellulr constituents (36, 39). Furthermore, the concentrtions of these gents in the mjor orgns of excretion, such s the liver nd kidney, hve been sid to correlte poorly with their reltive lipophilicity (36). We hve exmined four tetrcyclines of mrkedly different lipophilicity to compre their phrmcokinetic behvior in the mjor orgns of excretion nd their penetrtion into sites of notoriously poor ccess. As shown in dt from other studies (Tble 5), the extent of protein binding of minocycine by cnine serum is similr to tht of doxycycline nd tetrcycline, despite their disprte lipid solubilities. This fct simplified the interprettion of our own dt since it eliminted the influence of this vrible. There is no correltion between the pk vlues of the vrious tetrcyclines nd their prtition coefficients; indeed, the pprent dissocition constnts of the four gents re quite similr, except for minocycline, which displys second dimethylmino group with

5 VOL. 8, 1975 LIPOPHILICITY AND PHARMACOLOGICAL BEHAVIOR 717 TABLE 4. Concentrtion grdients of tetrcyclines in vrious cnine tissues nd body fluids Tissue or body fluid Concn grdient:b Minocycline Doxycycline Tetrcycline Oxytetrcycline Kidney Present studyc Other studies 10 (21) 22 (36) (20) 4 (36) Urine Present study Liver Present study Other studies 16 (21) 16 (36) 10 (20) 3 (36) Bile Present study Other studies d (21) 75d (20) 4 (39) Ileum Present study Other studies 8 (21) (12, 20) Cerebrospinl fluid Present study <0.27 <0.06 Other studies 0.4 (21) 0.4 (20, 22) Brin Present study <0.27 <0.06 Other studies 2.6 (21) 0.2 (20) Aqueous humor Present study <0.27 <0.06 Other studies 0.4 (21) (20) Vitreous humor Present study <0.27 <0.06 Other studies 0.6 (21) 0.5 (20) Numbers in prentheses indicte references; dt in itlics re those obtined in the present study. b) Level of drug in indicted site (microgrms per grm or microgrms per milliliter)/level of free (unbound) drug in serum (microgrms per milliliter). This ltter vlue hs been determined by multiplying the concentrtion of totl drug in serum by: minocycline, 0.25; doxycycline, 0.18; tetrcycline, 0.20; nd oxytetrcycline, c Dt re for renl cortex. Vlues for medull were: minocycline, 11; doxycycline, 25; tetrcycline, 26; oxytetrcycline, 9. d Gll bldder bile. TABLE 5. Selected spects of the cnine phrmcology of four tetrcyclines Serum protein binding Tetrcycline Tetrcyclie (96) Prenterl dose (%) excreted in: Urine Feces Bile Minocycline 75b 6-15 (21, 28) 80-90c (21) Doxycycline 82 (39) (37, 39) 75 (37) 3 (37) Tetrcycline 80 (39) 56 (28) Oxytetrcycline 27 (39) 53 (39) 1.8 (39) Numbers in prentheses indicte references. b Personl communiction, R. R. Roepke, Lederle Lbortories, Perl River, N. Y. c Includes biliry excretion.

6 718 BARZA ET AL. pk. of bout 5 (4, 24). This peculirity my contribute to the greter lipophilicity ofminocycline t neutrl ph (4). The results of the present investigtion indicte tht certin phrmcologicl properties of the tetrcyclines correlte closely with their reltive lipophilicity. Among the most striking ws the inverse reltion of lipid solubility with urinry excretion nd bsolute renl extrction of the tetrcyclines. The reson for this correltion is not cler since elimintion of these gents by the kidney is believed to occur solely by glomerulr filtrtion (29, 30), nd differences in protein binding cnnot ccount for the findings. One explntion might be bck diffusion of the more lipophilic congeners from the tubulr lumen (40), possibility tht is supported in prt by the fct tht the disprity in the levels of ntibiotic in the renl cortex ws much less thn tht in the urine. The levels of totl drug in rteril plsm lso showed striking correltion with lipophilicity. We re reluctnt, however, to infer direct reltion from this observtion since these concentrtions re the result of number of fctors tht were not exmined in the present study, including the extent of serum protein binding, rte of elimintion, nd volume of distribution of the ntibiotic. Indeed, the clculted levels of free minocycline, doxycycline, nd tetrcycline in the serum were virtully identicl. Biliry excretion of the four tetrcyclines, when expressed s the concentrtion grdient (Tble 4), showed n excellent correltion with lipid solubility. The reltion between lipophilicity of compound nd its biliry excretion is by no mens cler (33); in fct, in one study of penicillins in rodent model, n inverse reltion between the two functions ws noted (31). A mrked permissive effect of lipophilicity ws evident in the penetrtion of ntibiotics cross the blood-brin nd blood-oculr brriers. Minocycline nd doxycycline chieved concentrtions 0.7 to 2.8 times the level of free drug in the serum, wheres oxytetrcycline nd tetrcycline were undetectble. Levels of drugs or their concentrtion grdients in the heptic prenchym nd in renl cortex correlted poorly with lipophilicity. In contrst, the levels of ntibiotics in the renl medull (Fig. 2) exhibited n excellent inverse correltion with lipid solubility of the drug. It is not possible to determine the extent to which urinry ntibiotic, within the collecting ducts of the medull, contributed to this finding. With the exception of bsolute renl extrction, there ws no correltion between lipophilicity nd TABLE 6. Tetrcycline ANTIMICROB. AGENTS CHEMOTHER. Concentrtions of tetrcyclines (pg/mi) in contents of ilel loops Solution in ilel loop Sline Gelusil (10%) Milk Minocycline 0.6 ± ± ± 1.0 Doxycycline 5.5 ± ± ± 11 Tetrcycline 2.4 ± ± ± 0.9 Oxytetrcycline 4.2 ± ± ± 1.6 Men nd stndrd error of concentrtions during the lst hlf of h 3 of infusion of ntibiotic; ech drug ws dministered to five dogs. percent extrction or bsolute extrction by the liver or kidney. Doxycycline displyed mrked propensity to ccumulte intrluminlly in ilel segments contining milk. Such ccumultion presumbly is the result of the reltively high lipophilicity of doxycycline, permitting its pssge cross the intestinl mucos, nd its tendency to form complexes with polyvlent ctions of metls (41); moreover, the observtion is in ccord with the finding tht substntil mounts of doxycycline my be pssively trnsported from the serum into the intestinl lumen of dogs (37), rts (38), nd humns (41). Although the dt of Tble 1 suggest tht doxycycline is somewht less redily chelted by clcium thn is oxytetrcycline or tetrcycline, other work indictes tht t pproximtely neutrl ph, the tetrcyclines re lmost completely chelted by ll polyvlent metllic ctions studied (1, 2, 4). Of interest is the observtion tht the clcium cheltion product of doxycycline but not of minocycline or tetrcycline forms n insoluble precipitte t ntibiotic concentrtions of 5 nd 20,Ag/ml (J. Krueger, Lederle Lbortories, personl communiction). This my explin the unique propensity of doxycycline to ccumulte intrluminlly in milk-contining loops of ileum. The reson for the filure of doxycycline to become concentrted in loops filled with 10% Gelusil is not cler. One prtil explntion is the fct tht luminum hydroxide, t neutrl ph, presents virtully no free luminum to bind the ntibiotic. Since the tetrcyclines re not metbolized to ny importnt extent in dogs (19, 21, 37), our dt leve unnswered the question of the nonrenl routes of elimintion of minocycline. Although minocycline is strikingly more lipid soluble thn doxycycline, especilly in terms of its chloroform-wter prtition coefficient (Tble 1), the only respects in which the two compounds exhibited phrmcologicl differences were in their urinry excretion, levels in renl

7 VOL. 8, 1975 LIPOPHILICITY AND PHARMACOLOGICAL BEHAVIOR 719 TABLE 7. Selected spects of humn phrmcology offour tetrcyclines Serum protein Prenterl dose ex- Concn grdient" Tetrcycline binding (%) creted in urine (%) Bile Cerebrospinl fluid Minocycline 76 (25) 6-9 (7, 10, 25) 150 (25) (6, 25) Doxycycline (10) 35 (3, 10) (11) (25, 26) Tetrcycline (10) 60 (23) (11) (14, 32, 42) Oxytetrcycline (10) 70 (23) (11) (15, 17, 42) Numbers in prentheses indicte references. b Concentrtion of drug in vrious sites (microgrms per milliliter)/concentrtion of free (unbound) drug in serum (microgrms per milliliter). The following frctions were used to compute the serum level of unbound drug: minocycline, 0.24; doxycycline, 0.18; tetrcycline, 0.40; oxytetrcycline, cortex, nd ccumultion in the lumen of ilel segments contining milk. In ddition, levels of minocycline in the brin were lmost threefold those of doxycycline, lthough the differences were not quite significnt (P = 0.05 to 0.1). This finding is of interest in view of the pprent cpcity of minocycline to produce vestibulr disturbnces (27). The octnol-wter prtition coefficient ppered to correlte somewht better thn the chloroform-wter prtition coefficient with the in vivo behvior of minocycline nd doxycycline. Although the octnol-wter system hs been regrded s good model for the study of pssge cross membrnes, the reltions involved re exceedingly complex nd re best expressed logrithmiclly (13). We re, therefore, reluctnt to drw ny conclusion s to which type of prtition coefficient correltes best with the phrmcologicl behvior of these gents. Even though loding dose of ntibiotic ws dministered in these studies, it is possible tht distribution equilibrium ws incomplete t the end of the 3-h period of infusion. The fct tht most indices were stble by 3 h suggests tht the differences noted mong the gents would probbly persist t full equilibrium. The vlidity of our findings is further supported by the generl greement of the results with those of others (Tble 4), despite differences in experimentl techniques. In Tble 7, dt concerning selected spects of the phrmcology of tetrcyclines in humns hve been compiled. The results re similr to those in dogs, with mrked inverse correltion between lipophilicity nd urinry excretion of the tetrcyclines nd direct correltion between the concentrtion grdients in bile nd cerebrospinl fluid. The results of these studies support the notion tht lipophilicity correltes well with certin properties oftetrcyclines. Although we were unble to show strictly liner correltion between the lipid-wter prtition coefficient (or its logrithm) nd ny of the phrmcologicl mesurements observed with these ntibiotics, it seems likely tht such reltion would hold for certin nonspecilized tissues, such s muscle (36). There is n inverse reltion of lipophilicity with renl extrction, excretion, nd medullry concentrtion of the ntibiotics nd direct one with the biliry concentrtion grdient nd penetrtion of the blood-brin nd blood-oculr brriers. In contrst, the heptic uptke of the drugs nd the concentrtions of ntibiotic in the liver nd in renl cortex show little reltion to lipid solubility. The cpcity of doxycycline to ccumulte in segments of ileum contining milk suggests tht this route of elimintion my be peculir to this congener nd my be strongly influenced by the nture of the chelting substnce present intrluminlly. ACKNOWLEDGMENTS This work ws supported by grnt from Lederle Lbortories, Perl River, N. Y. We re indebted to Ptrici Roche for vluble ssistnce throughout these studies. We re most grteful to Jmes Krueger nd Robert Kelly for helpful dvice nd criticism. LITERATURE CITED 1. Albert, A Avidity ofterrmycin nd Aureomycin for metllic ctions. Nture (London) 172: Albert, A., nd C. W. Rees Avidity of the tetrcyclines for the ctions of metls. Nture (London) 177: Alestig, K Studies on doxycycline during intrvenous nd orl tretment with reference to renl function. Scnd. J. Infect. Dis. 5: Brringer, W. C., W. Shultz, G. M. Sieger, nd R. A. Nsh Minocycline hydrochloride nd its reltionship to other tetrcycline ntibiotics. Am. J. Hosp. Phrm. 146: Brz, M., J. Brusch, M. G. Bergeron, 0. Kemmotsu, nd L. Weinstein Extrction of ntibiotics from the circultion by liver nd kidney: effect of probenecid. J. Infect. Dis. 131(Suppl.):S86-S Crney, S., R. A. Butcher, J. K. Dwborn, nd G. Pttison Minocycline excretion nd distribution in reltion to renl function in mn. Clin. Exp. Phrmcol. Physiol. 1:

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