Pharmacokinetics of Phenobarbital in the Cat FollowingIntravenous and Oral Administration

Susan M. Cochrane, William D. Black, Joane M. Parent, Dana G. Allen and John H. Lumsden

ABSTRACT RESUME INTRODUCTION

Phenobarbital was administered toeight healthy cats as a single intraven-ous dose of 10 mg/kg. Serum pheno-barbital concentrations were deter-mined using an immunoassaytechnique. The intravenous data werefitted to one-, two- and three-compartment models. After statisticalcomparison of the three models, atwo-compartment model was selected.Following intravenous administra-tion, the drug was rapidly distributed(distribution half-life = 0.046 ± 0.007h) with a large apparent volume ofdistribution (931 ± 44.8 mL/kg).Subsequent elimination of phenobar-bital from the body was slow (elimina-tion half-life = 58.8 ± 4.21 h).

Three weeks later, a single oraldose of phenobarbital (10 mg/kg)was administered to the same groupof cats. A one-compartment modelwith an input component was used todescribe the results. After oraladministration, the initial rapidabsorption phase (absorption half-life = 0.382 ± 0.099 h) was followed bya plateau in the serum concentration(13.5 ± 0.148 Ag/mL) for approxi-mately 10 h. The half-life of theterminal elimination phase (76.1 +

6.96 h) was not signifilcantly differentfrom the half-life determined for theintravenous route. Bioavailability ofthe oral drug was high (F = 1.20 +0.120).Based on the pharmacokinetic

parameters determined in this study,phenobarbital appears to be a suitabledrug for use as an anticonvulsant inthe cat.

Du phenobarbital (10 mg/kg) a eteinjecte en une seule dose par voieintraveineuse a huit chats sains. Lesconcentrations seriques de phenobar-bital ont ete determinees par immu-noessais. Les donnees ont tente d'etreajustees selon des modeles 'a un, deuxou trois compartiments; le modele 'adeux compartiments a ete celuidecrivant le mieux la cimetique duproduit. Suite a l'injection intravei-neuse, le medicament s'est rapidementdisperse (demi-vie de la distribution,0,046 ± 0,007 h) dans un volumeapparent de distribution de 931 ± 45mL/kg. Par la suite, l'eliminationcorporelle du produit a ete lente(demi-vie, 58,8 ± 4,2 h).

Trois semaines plus tard, une seuledose orale de phenobarbital (10 mg/kg) a ete donnee aux memes ani-maux. Un modele a un compartimentavec une composante ajoutee s'estrevele comme celui decrivant lemieux les resultats obtenus. Apres laphase d'absorption rapide (demi-vie,0,382 ± 0,099 h), les concentrationsseriques (13,5 ± 0,1 ,g/mL) ontatteint un plateau pendant pres de dixheures. De son cote, la demie-vie de laphase d'e'limination (76,1 ± 6,9 h) n'apas e 't significativement diffe-rente de celle observee lors del'injection intraveineuse. La biodis-ponibilite du produit administre peros a ete elevee (F = 1,20 ± 0,12).Selon l'etude de la pharmococine-tique du phenobarbital chez le chat, ilsemble que ce produit pourrait etreemploye avantageusement commeanticonvulsivant chez le chat.

Seizure disorders represent one ofthe most common problems in smallanimal neurology (1). Seizure activityis reported to occur in approximately0.5-1% of feline and canine patients(2,3). This is similar to the incidencereported in humans (4,5). In contrastto the dog, where idiopathic epilepsy isa common cause of seizures (6,7), inthe cat convulsions are more likely toreflect a structural, and often intra-cranial disease such as neoplasia,inflammation or degeneration (8,9).

Limited information is available onthe use of anticonvulsants in the cat(2). Neither phenytoin nor primidonehave been recommended in thisspecies because of their potentialtoxicity and difficulty in establishing asafe dosage regimen (3,10,11).Authors have recommended pheno-barbital (PB), and more recentlydiazepam, as the anticonvulsants ofchoice for long-term therapy in the cat(8,12). Despite these recommenda-tions, minimal pharmacokinetic dataare available. Frey (2) reported a half-life of 34-43 h following chronic PBtreatment in cats.The objectives of this study were to

select the appropriate model and todetermine the pharmacokinetics of PBafter administration of a singleintravenous and oral dose in the cat.

MATERIALS AND METHODS

EXPERIMENTAL ANIMALS

Eight mixed breed cats (6 male, 2female) ranging in age from approxi-

Can J Vet Res 1990; 54: 132-138

Department of Clinical Studies (Cochrane, Parent, Allen), Department of Biomedical Sciences (Black) and Department of Pathology (Lumsden),Ontario Veterinary College, University of Guelph, Guelph, Ontario NIG 2W1.This study was funded by the Ontario Veterinary College Pet Trust.

Submitted June 13, 1989.

132

mately one to three years were used inthis experiment. The cats weighedfrom 2.6 to 6.0 kg (mean weight 4.35kg). Prior to the study, physicalexamination, hematological evalua-tion, serum biochemistry analysis(Coulter Dacos, Coulter Electronicsof Canada, Burlington, Ontario) andfecal parasite egg count were per-formed to demonstrate that each catwas healthy. Throughout the experi-ment the cats were housed in individ-ual metal cages in a room isolatedfrom other cats and were fed commer-cial dry cat food (Meow Mix®,Ralston Purina, Mississauga, Onta-rio) and water ad libitum. The catswere fasted of food for 12 h prior toand following drug administration.The guidelines of the Guide to theCare and Use of Experimental Anim-als of the Canadian Council onAnimal Care were followed.

SURGICAL PROCEDURES

To facilitate blood collection withminimal stress to the cat during theintravenous (IV) and oral studies, anindwelling jugular catheter (16 or 19gauge, 20.3 cm Intracath, Deseret Co.,Sandy, Utah) was placed as previouslydescribed (13).To induce anesthesia, the cats were

placed in a 5 L airtight plexiglass boxcontaining isoflurane (AErrane®,Anaquest, Pointe Claire, Quebec) andoxygen. They were then intubated andmaintained at a light surgical plane ofanesthesia during catheterization.The catheter was removed after the

IV study and another catheter placedin the opposite jugular vein prior tothe oral experiment.

INTRAVENOUS PHENOBARBITALSTUDY

Two days following placement ofthe jugular catheter a single dose of 10mg/kg of phenobarbital sodium USP(Luminal®, Abbott Laboratories,Toronto, Ontario) was administeredinto the cephalic vein using a butterflyapparatus (Venisystems Butterfly-23,Abbott Ireland Ltd., Ireland), fol-lowed by flushing with sterile saline(1.0 mL). The PB dose was selected toallow for sufficient points on the curveto be measured accurately by the assayprocedure. Blood samples (0.5 mL)were collected at 0, 1, 2, 3, 4, 5, 10, 15and 30 min, 1, 2, 3,4,6, 10,24, 48, 72

and 96 h after injection. To avoidcollecting the residual volume of thecatheter, 0.5 mL of blood was drawnand discarded prior to sampling. Tomaintain patency, 0.5 mL of heparinsolution (100 U/mL) was injected intothe catheter following each of the lastfive samples.To evaluate the effect of sampling,

hemoglobin, total protein level andhematocrit were determined at the 10,24 and 96 h intervals. Following thefinal sample, the catheter wasremoved.

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ORAL PHENOBARBITAL STUDY

Three weeks following the IV study,blood samples were drawn from eachcat for hematological evaluation andserum biochemistry analysis. Ajugular catheter was placed undergeneral anesthesia as previouslydescribed (13). Two days later, the oralPB study was initiated.

Phenobarbital tablets (Phenobarbi-tal acid USP, Parke-Davis, Scar-borough, Ontario) were administeredorally as a single dose of 10 mg/kg.

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Fig. 1. Serum concentrations of phenobarbital (T mean ± SEM) following administration of asingle intravenous dose of 10 mg/kg in eight cats; A) 0-60 min, B) 0-96 h.Predicted Curves:One-compartment model ( . ) Two-compartment model (--------)Three-compartment model ( II

133

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The tablets were cut and weighed toensure an accurate dose. Bloodsamples were collected as describedfor the IV study at 0, 5, 10, 15, 30 and45 min, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24,48, 72, 96 and 120 h after PBadministration. Heparin solution wasinjected as previously described for theIV study, following each of the last sixsamples. Hematological evaluationand serum biochemistry analysis wasrepeated following the 120 h samplecollection.

PHENOBARBITAL ASSAY

The blood sample was allowed toclot. The serum was separated bycentrifugation (15 min at 1239 g) andthe serum analyzed within I h ofcollection.

Analysis was performed by animmunoassay technique (Seralyzer®Aris, Ames Division, Miles Laborato-

ries Ivalidasampli(0, 7.5normadupliccurve.PB st0.9857cient (Ast

providassayesamplhtion f(range4

During cross-reactivity studies, themajor metabolite p-hydroxypheno-barbital did not cross-react or inter-fere with the assay (Technical Infor-mation, Seralyzer® Aris, AmesDivision, Miles Laboratories Inc.,Elkhart, Indiana).DATA ANALYSIS

Logarithmic serum concentra-tions of PB were plotted against time(linear) for both IV and oral studies(Figs. 1 and 2). The terminalelimination slope of each graph was

8#-,-.- lanalyzed by least squares regressionanalysis (14). The remaining compo-nents of the curve were isolated usingthe method of residuals (15) andanalyzed by least squares regressionanalysis (14).The intravenous PB serum levels

were fitted to one-, two- and three-compartment models (15) and thepredicted curves were plotted (Fig.1). Selected pharmacokineticparameters obtained for each modelwere compared (Table I) using one-way analysis of variance (ANOVA)and least significant differences(LSD) (14).The two-compartment model (Cp =

Ae- at + Be- bt) was chosen for detailedpharmacokinetic analysis. The phar-macokinetic parameters were calcu-lated using standard equations (15,

SEM) following a single oral dose of 10 16). These parameters are defined inTable II. The maintenance dose wascalculated using the formula:

Maintenance dose FQB) x desired

Inc., Elkhart, Indiana). To serum concentration x T, where T =Lte this procedure for the cat, dosing interval (17).es of known PB concentration Pharmacokinetics of PB adminis-, 15, 30, 60 and 120 Ag! mL) in tered orally were determined using ail cat serum were analyzed in one-compartment model with an,ate to establish a standard input component (15). The pharmaco-The equation of the line for the kinetic parameters were calculated astandard curve was -0.0958 + previously described (15,16) and are7(X) and the correlation coeffi- defined in Table III.r) was 0.9993. The half-life data for IV and oralLandr) izdwastrol .g/ administration were compared forandardized control (30,Mg! mL) individual animals using a pairedled by the manufacturer was Student's t-test (14).d prior to each group of Statistical analyses were performedes. If the calculated concentra- at a confidence level of 95%. All dataor the control was outside the are presented as mean ± standardof 28-32 Mug/ mL, the instrument error of the mean (SEM).-,al;lsnAVs. o;*...cm A1- _ Dwas reca1iUraLea using Known IB

standards of 10 and 50 ,ug/mLsupplied by the manufacturer. Thecoefficient of variation (CV) for theappropriately calibrated 30 Ag/mLcontrol for the entire experimentalperiod was 3.75%.

RESULTS

Hematological and serum biochem-ical data determined prior to the IVand oral studies and at completion ofthe oral study were within normal

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TABLE I. Comparison between pharmacokinetic parameters determined by one-, two- and three-compartment models following a single IV dose of phenobarbital in the cat*

B b A a P pModel n (Mg/ mL) (h-') (jg/ mL) (h-') (#g/ mL) (h')I-C 8 13.6a 0.016a

±0.560 ±0.0012-C 8 10.9b 0.013b 18.6a 17.3a

±0.500 ±0.001 ±1.91 ±2.213-C 7+ 10.6b 0.012b 4.50b 2.58b 15.3 25.9

±0.602 ±0.001 ±1.17 ±0.615 ±2.73 ±4.50*Values expressed as mean ± SEM

a,bDifferent superscripts in vertical columns indicate significant difference between derivedparameters+One cat did not fit a three-compartment modeln = number of catsC = compartmentB = y-intercept elimination curveb = overall elimination rate constantA = y-intercept distribution curvea = distribution rate constant (peripheral compartment)P = y-intercept distribution curvep = distribution rate constant (peripheral compartment)

ANOVA and LSD (14) (Table I). They-intercept of the terminal eliminationcurve (B) and the slope of theelimination phase (b) for the two- andthree-compartment models weresignificantly less than for the one-compartment model. However, whenthe y-intercept and elimination slopeof the two- and three-compartmentmodels were compared, they were notsignificantly different.The y-intercept (A) and distribution

slope (a) for the two- and three-compartment models were signifi-cantly different (Table I). P and pvalues were reported for the three-compartment model.The pharmacokinetic parameters of

PB following a single IV dosedetermined by the two-compartmentmodel are presented in Table II.

ranges as established at the OntarioVeterinary College. When values forthe individual cats were comparedduring the experiment using a pairedStudent's t-test, no significant differ-ences were present, suggesting thatsample collection did not alter bloodparameters.The correlation coefficient of the

standard curve indicated that theassay was linear over the concentra-tion range used in the study. The lowCV for the standard control (30 ,g!mL) indicates that the repeatability ofthe analytical procedure betweensample runs was high.

INTRAVENOUS PHENOBARBITALSTUDY

The logarithmic serum drug con-centrations measured following IVadministration of PB were plottedagainst time (linear) (Fig. 1).When the curves predicted for the

one-, two- and three-compartmentmodels were plotted (Fig. 1), the curvefor the three-compartment modelappeared to best describe the serumPB data. The difference between thetwo- and three-compartment modelswas most evident at the 10 to 30 minpoints.When the terminal elimination

slope was evaluated, the correlationcoefficient (r) for data points indicateda better fit of the data to the curves ofthe two-compartment (0.976) andthree-compartment (0.983) models

than for the one-compartment model(0.848)To further assess selection of an

appropriate model, the y-intercepts(A,B,P) and slopes of the curves(a,b,p) determined for each modelwere compared using one-way

ORAL PHENOBARBITAL STUDY

The logarithmic serum drug con-centrations following oral administra-tion of PB were plotted against time(linear) (Fig. 2). The data were fitted toa one-compartment model with aninput component. The pharmacoki-netic parameters of PB following

TABLE II. Pharmacokinetic parameters following a single intravenous dose of phenobarbital(10 mg/kg) in eight cats based on two-compartment model

Parameter Mean SEM Range

C°p (,ug/mL) 29.5 1.92 21.1 - 35.4A (,ug/mL) 18.6 1.91 9.22 - 23.9B(Ag/mL) 10.9 0.50 8.77- 12.7a (h-I) 17.3 2.21 8.76 - 26.8b (h-') 0.013 0.001 0.009 - 0.017t¼2a (h) 0.046 0.007 0.026 - 0.079t'/2b (h) 58.8 4.21 41.3 - 77.0k,2 (h-) 10.7 1.56 5.92 - 18.6k21 (h-') 6.58 0.966 2.81 - 10.5kel (h-I) 0.033 0.002 0.022 - 0.039Vc(mL/kg) 351.0 26.8 282.4 - 467.3V'd(area) (mL/kg) 931.1 44.8 784.2- 1138.9Cl(B)(mL/kg/h) 11.3 0.76 7.68 - 14.4AUC (,ug h/mL) 918.9 69.3 656.9 - 1301.5Weight (kg) 4.35 0.388 2.6 - 6.0

CO p = theoretical serum level immediately after injectionA = y-intercept distribution curveB = y-intercept elimination curvea = distribution rate constantb = overall elimination rate constantt½/2a = half-life distributiont /2b = half-life eliminationk12 = transfer constant (central to peripheral)k2, = transfer constant (peripheral to central)kel = elimination rate constant from central compartmentVc = apparent volume of distribution central compartmentV'd = apparent volume of distribution at equilibrium (area method)Cl(B) = total body clearance from plasmaAUC = area under plasma concentration-time curve (0 to infinity)

135

TABLE III. Pharmacokinetic parameters following oral administration of phenobarbital (10 mg/kg)in eight cats

Parameter Mean SEM Range

B'(pg/mL) 13.9 0.711 11.0- 16.6Kab (h-') 2.56 0.581 0.672 - 5.04b (h-1) 0.010 0.0001 0.007 - 0.015t½/2ab (h) 0.382 0.099 0.157 - 1.03t½/2b (h) 76.1 6.96 46.2 - 96.3V'd(area)(mL/ kg) 727.6 37.9 598.7 - 904.5Cl(B)(mL/kg/h) 6.97 0.598 4.66 - 9.10AUC(ugh/mL) 1518.07 139.3 1151.7 - 2145.2F 1.69 0.172 1.28 - 2.51F* 1.20 0.120 0.82- 1.79Wt (kg) 4.94 0.438 3.0 - 6.0

B' = y-intercept elimination curveKab = rate of absorptionb = overall elimination rate constanttl/2ab = half-life absorptiontI / 2b = half-life eliminationV'd = apparent volume of distribution at equilibrium (area method)CI(B) = total body clearance from plasmaAUC = area under plasma concentration-time curve (0 to infinity)F = fraction absorbedF* = F corrected for drug form and intraindividual variationWt = body weight of animal

administration of a single oral dose arepresented in Table III.The duration of the initial rapid

absorption phase was approximately 1to 1.5 h. The serum PB concentrationthen remained relatively constant forapproximately 10 h. The mean serumdrug concentration calculated duringthis time interval from 2-12 h was 13.5+ 0.148 ug/mL (Fig. 2).The bioavailability of oral PB was

high (F = 1.69 ± 0.172). This value wasreduced to 1.20 ± 0.120 whencorrections were made for intraindi-vidual variability in the overallelimination rate from the body (16),and for differences in the molecularweight of the PB sodium salt (IV) andPB acid (oral) (18).

DISCUSSION

Previous reports have described thedisposition kinetics of PB after IVadministration using a one-compartment model in dogs (19), atwo-compartment model in horses(20,21) and humans (22) or a one- andtwo-compartment model in dogs (23).In the present study, sample collectionat 1 min intervals for the first 5 minafter IV drug administration andfrequently thereafter enabled detec-tion of three compartments. Thepredicted curve of the three-

compartment model appeared to bestdescribe the data (Fig. 1). However,when the parameters B and b, whichare both important in determining atherapeutic regime, were calculated bythe two- and three-compartmentmodels, they were virtually the same(Table I). Therefore, it was decidedthat the simpler two-compartmentmodel could be used for detailedpharmacokinetic analysis.The elimination half-life following

IV administration of PB in cats waswithin the range reported for dogs [32h (23) to 92.6 h (19)], and shorter thanone report in humans [99 h (22)]. Incontrast, the t½2b for adult horses was18.3 h (21) and for neonatal foals was12.8 h (24).The high V'd suggests a wide

distribution of PB within the body(16). This value is larger than reportedfor dogs (631.0 mL/kg) (25) butsimilar to humans (700-1000 mL/kg)(26) and horses (803 mL/kg) (21). Thehigh lipid solubility of PB and lowlevel of ionization at physiological pH(pKa 7.3) probably contribute to thehigh V'd observed (27). These charac-teristics allow the drug to readilydiffuse across body membranes suchas the blood-brain barrier (27). In fact,sequestration ofPB within brain tissuehas been demonstrated (28).

Phenobarbital administered orallywas rapidly absorbed with peak serum

concentrations achieved in approxi-mately 1 to 1.5 h following administra-tion. Previous reported times to reachmaximum serum concentrationsranged from 1.5 h (29) to 6 h (30) indogs and 1.5 h (22) to 9-12 h (31) inhumans.The serum PB concentration

remained relatively constant forapproximately 10 h after the rapidabsorption phase. A similar plateauhas been observed in dogs (17,19) andhumans (22,32) after oral PB. Itsuggests that input of the drug toserum from the gastrointestinal tract(GIT) is being balanced by losses dueto distribution within the body andelimination. The plateau may alsoindicate a relatively constant rate ofGIT uptake for the 10 h period.Factors such as tablet disintegration,dissolution and dispersal may influ-ence uptake from the digestive tract. Itis unlikely that tablet disintegrationdelayed absorption, since studies inour laboratory showed this product todisintegrate rapidly (approximately1-2 min). Harvey (27) suggested thatthe rate-limiting step in PB absorptionmay be dissolution and/or dispersalwithin the GIT.A one-compartment model ade-

quately described the eliminationphase following administration of anoral dose of PB (Fig. 2). A smalldistribution component was evident inthe data but there were insufficientdata points to adequately analyze thissection of the curve. This did notappear to seriously interfere withselection of the model since there wasan excellent fit of the data to theterminal part of the curve predicted bythe one-compartment model.The decline in serum PB concentra-

tions following oral administrationwas slow. This is longer than reportedfor oral PB in adult horses (19.0 ± 4.4h) (20) and dogs (44-62 h) (30), butsimilar to humans (81.6 ± 25 h) (33).The elimination half-life following asingle oral dose of PB was notsignificantly different from the IVexperiment. With long-term anticon-vulsant therapy, a prolonged elimina-tion half-life is an advantage since lessfrequent drug administration isrequired to maintain relatively con-stant tissue levels (16).

Both V'd and Cl(B) values deter-mined following oral administration

136

were lower than for the IV study. Sinceboth parameters include AUC in theircalculation, the differences appear toreflect the consistently larger AUC fororal PB. In addition, the bioavailabil-ity (F) determined by comparing AUCoral and AUC IV (16) exceeded 1.00.The F value was corrected fordifferences in the molecular weight(MW) of the drug formulations usedin the study. The MW of PB sodium(254.22) administered IV is larger thanthe MW of PB acid (232.32) givenorally (18). To compare the IV andoral studies, the IV serum levels weremultiplied by a factor of 1.095(254.22/ 232.32) (22,33). Furthercorrection for intraindividual variabil-ity in the overall elimination ratebetween the IV and oral studies (16)yielded a final F value of 1.20 ± 0.120.

Bioavailability data for oral PBhave been reported in other speciesincluding dogs (19), humans (22) andhorses (20). It is of interest thatauthors using PB sodium for both oraland IV studies have reported F valuesin excess of 1.0 (19,20,22). Forexample, Ravis et al (20) determined Fvalues as high as 1.24 in the horse.One possible explanation for the

high F value is the administration ofless drug IV than orally. To ensurethat none of the calculated dose waslost during IV injection, PB levels weredetermined before and after passagethrough the syringe and cathetersystem. No evidence of PB loss withinthe injection system could be demon-strated and the amount of drug was asindicated on the label.

Since PB excretion is enhanced inalkaline pH, another possible expla-nation for the high F value was anelevated urinary pH (34). No signifi-cant difference in urinary pH betweenthe oral and IV studies wasdocumented.

Administration of a larger dosethan expected orally could influencethe calculated bioavailability.Although the manufacturer assured usthat the quantity of drug in the tabletswas as indicated on the label, the exactamount could have varied since theUnited States Pharmacopeia regula-tions consider a range of 90 to 110% ofthe labelled amount of PB acceptable(35). We were unable to determineaccurately the concentration of drugin the tablets using our assay proce-

dure due to the compounding mate-rials in the tablets. The reason for theapparent excess bioavailability fororal PB remains unknown andrequires further investigation.A maintenance dose was calculated

using the formula of Ravis et al (17).Based on a desired midtherapeuticsteady state serum concentration of 25.tig/ mL (17,36-38) and treatment every24 h, a PB dose of 4.2 mg/ kg would berequired.Time to reach a steady-state serum

concentration is normally consideredto be five half-lives (16). Approxi-mately 16 days would be required toachieve a steady state PB concentra-tion in the cat. In cases where it isdesirable to achieve steady state morerapidly, a loading dose of PB could beadministered.The maintenance dose calculated in

this study assumes that the eliminationkinetics for PB do not change afterrepeated administrations. AlthoughPB is a potent inducer of hepaticmicrosomal enzyme function (39), amultiple dose study is required beforethe influence of induction on theelimination kinetics can be evaluated(40,41).

In summary, the pharmacokineticsof PB suggest that once daily treat-ment at the suggested dose shouldresult in adequate therapeutic serumconcentrations. It is, however, recom-mended that serum PB concentrationsbe monitored with long-term anticon-vulsant therapy, since the influence ofrepeated treatments on the elimina-tion kinetics is not yet known.

ACKNOWLEDGMENTS

The authors wish to thank JeanClaxton for her excellent technicalassistance and guidance when per-forming the kinetic analysis and forthe use of her computer programs.

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