animals : all animals were maintained in accordance with the recommendations of the  guide for 
 the care and use of laboratory animals approved by the ethics committee of the faculty of agriculture , tokyo 
 university of agriculture and technology ( approval number 76/2013 ) . five clinically healthy male shiba goats 
 bred and maintained at fuchu campus of tokyo university of agriculture and technology , weighing 2560 kg and 
 aged 23 years , were used in this study . these goats were housed in pens at an ambient temperature and with good 
 ventilation . animals were fed hay cubes ( # 1a cubes , eckenberg farms inc . , mattawa , wa , u.s.a . ) at 0.8 kg / head 
 twice a day . chemicals and reagents : sdd was obtained from mp biomedicals , llc ( rue geiler de kaysersberg 
 illkirch cedex , france ) . sulfadimethoxine was obtained 
 as a sodium salt from daiichi sankyo pharmaceutical co. ( tokyo , japan ) . all other reagents and chemicals used in 
 the present study were of hplc or analytical grade and obtained commercially . pharmacokinetic study : sulfonamides solutions ( 100 mg / ml ) were prepared in 
 sterilized distilled water . for sdz , this was done by dissolving the sodium salt ; the other two sulfonamides 
 ( smz and sa ) were dissolved in water by adding a few drops of diluted ( 1n ) sodium hydroxide solution . they 
 were administered either into the left jugular vein or orally to five male goats at doses of 10 mg ( 0.1 
 ml)/kg body weight , using a crossover design with at least a 3-week washout period . the 
 dose ( 10 mg / kg ) was chosen for avoid unwanted effect ( anorexia , diarrhea , etc . ) to goats . oral administration 
 was carried out using a nasogastric catheter , which was flushed with 60 ml tap water after 
 dosing . blood ( 3 ml ) was collected 
 from the right jugular vein immediately prior to the treatments , 1 , 2 , 4 , 6 , 9 , 12 and 24 hr after the 
 intravenous injections , and 1 , 2 , 4 , 6 , 9 , 12 , 24 , 32 and 48 hr after their oral administration . plasma was 
 separated by the centrifugation of blood at 1,600 g for 10 min and stored at 20c until 
 analyzed . stability of sulfonamides in the rumen juice : two male shiba goats of five goats used for a 
 pharmacokinetic study were restrained , and nasal catheters were passed into the rumen . thereafter , 
 approximately 50 ml of rumen juice was aspirated through the catheter from each animal . the 
 rumen juices ( ph 6.5 ) of two goats were combined and processed for incubation immediately after its 
 collection . fifty microliters of the sdd , sdz or sa solution ( 200 g / ml ) was 
 added to 950 l of the rumen fluid to give a final concentration of 10 
 g / ml of the incubation mixture . five samples of each drug were prepared 
 and incubated in a thermostatic shaking water bath at 39c for 24 hr under anaerobic conditions . octanol - buffer ( ph 6.5 ) partitioning experiments : octanol - buffer partitioning studies were 
 performed using a shake flask method as recommended by the organization for economic cooperation and 
 development ( oecd ) . before partitioning , the two solvents were 
 mutually saturated at 25c for 24 hr . solutions of the three sulfonamides ( 10 
 g / ml ) were prepared in the octanol - saturated buffer . these solutions were 
 then equilibrated at 25c with an equivalent , double and half volume of buffer - saturated octanol . equilibration was achieved by hand shaking of the funnels ( by 
 rotation of the funnels through 180 degrees about its transverse axis approximately one hundred times in five 
 min ) allowing the trapped air to rise through the two phases . the funnels were then fixed vertically by 
 racking until complete separation of the two phases . the buffer phase was collected and centrifuged at 1,600 
 g for 10 min at 25c , and the supernatant octanol phase was discarded . the drug 
 concentration in the buffer phase was then determined by hplc , while that in the octanol phase was calculated 
 from the difference between the initial and final concentrations in the buffer phase . sdd , sdz and sa concentrations were determined in plasma , rumen juice and buffer samples by hplc with uv 
 detection . two hundred microliters of perchloric acid ( 0.5 m ) was added to 200 l of the 
 plasma sample . the mixture was vortexed for 30 sec and then centrifuged at 20,000 g for 10 
 min at 5c . fifty 
 microliters of the filtrate was injected into the hplc column . in the case of rumen juice samples , sdd , sdz and sa concentrations were determined after extraction with 
 ethyl acetate . after being incubated for 24 hr , 50 l of the internal standard ( 200 
 g / ml ) was added to the rumen juice samples . the internal standards used 
 in the present study were sulfadimethoxine , sa and sdz for sdd , sdz and sa , respectively . the mixtures were vortexed for 30 sec and then centrifuged at 
 3,000 g for 10 min at 5c . the obtained supernatants were transferred into pear - shaped flasks 
 and evaporated to dryness at 30c . the residue was reconstituted in 500 l of the mobile 
 phase and filtered using the 0.45-m hplc filter . the mobile phases used were a mixture of 50 mm acetate buffer ( ph 5 ) and acetonitrile ( 75:25 , v / v ) for sdd , a 
 mixture of 50 mm acetate buffer ( ph 4 ) and acetonitrile ( 75:25 , v / v ) for sdz , and a mixture of 50 mm acetate 
 buffer ( ph 5 ) and acetonitrile ( 80:20 , v / v ) for sa . analytical separation was accomplished using a 
 reversed - phase c8 column ( mightysil rp-8 gp , 4.6 m  250 mm , kanto chemical co. , 
 tokyo , japan ) . the recoveries of sdd , sdz and sa from plasma samples at 1 g / ml ( n=5 ) were 
 109.2  2.00% , 87.9  1.52% and 95.0  1.75% , while those from rumen juice samples at 10 
 g / ml ( n=5 ) were 83.5  2.06% , 84.3  2.09% and 88.1  2.35% , 
 respectively . the inter - day cv values for plasma samples ranged from 1.67 to 2.14% for sdd , 0.63 to 3.84% for 
 sdz and from 1.21 to 2.29% for sa , while those for rumen juice samples ranged from 1.86 to 2.79% for sdd , 1.96 
 to 5.24% for sdz and 1.61 to 3.57% for sa ( n=5 , 3 times ) . differences in the mean values between groups were analyzed by 
 scheff s multiple comparison test after a one - way anova single factor test . the plasma concentration - time curves of sdd , sdz and sa after their intravenous administration fit well with 
 the one compartment model . therefore , the curves obtained after the intravenous injections 
 ( cpiv ( t ) ) and those after their oral administration 
 ( cppo ( t ) ) were described by eqs . 1 and 2 , respectively . equations 1 and 2 were simultaneously fit to the plasma concentration - time curves after the intravenous 
 injections and oral administration to the same goats , respectively , in order to calculate pharmacokinetic 
 parameters by the nonlinear least - squares method using the curve fitting program , multi . the area under the 
 concentration versus time curve ( auc ) was calculated by the trapezoidal method ( from time zero to the last 
 sampling time ) and integration ( from the last sampling time to infinity ) . total body clearance 
 ( cltot ) , bioavailability ( f ) , mean residence time ( mrt ) , mean absorption time ( mat ) , elimination 
 half - life ( t1/2kel ) and distribution volume at a steady state ( vdss ) were calculated by 
 conventional methods . pharmacokinetic study : sulfonamides solutions ( 100 mg / ml ) were prepared in 
 sterilized distilled water . for sdz , this was done by dissolving the sodium salt ; the other two sulfonamides 
 ( smz and sa ) were dissolved in water by adding a few drops of diluted ( 1n ) sodium hydroxide solution . they 
 were administered either into the left jugular vein or orally to five male goats at doses of 10 mg ( 0.1 
 ml)/kg body weight , using a crossover design with at least a 3-week washout period . the 
 dose ( 10 mg / kg ) was chosen for avoid unwanted effect ( anorexia , diarrhea , etc . ) to goats . oral administration 
 was carried out using a nasogastric catheter , which was flushed with 60 ml tap water after 
 dosing . blood ( 3 ml ) was collected 
 from the right jugular vein immediately prior to the treatments , 1 , 2 , 4 , 6 , 9 , 12 and 24 hr after the 
 intravenous injections , and 1 , 2 , 4 , 6 , 9 , 12 , 24 , 32 and 48 hr after their oral administration . plasma was 
 separated by the centrifugation of blood at 1,600 g for 10 min and stored at 20c until 
 analyzed . stability of sulfonamides in the rumen juice : two male shiba goats of five goats used for a 
 pharmacokinetic study were restrained , and nasal catheters were passed into the rumen . thereafter , 
 approximately 50 ml of rumen juice was aspirated through the catheter from each animal . the 
 rumen juices ( ph 6.5 ) of two goats were combined and processed for incubation immediately after its 
 collection . fifty microliters of the sdd , sdz or sa solution ( 200 g / ml ) was 
 added to 950 l of the rumen fluid to give a final concentration of 10 
 g / ml of the incubation mixture . five samples of each drug were prepared 
 and incubated in a thermostatic shaking water bath at 39c for 24 hr under anaerobic conditions . octanol - buffer ( ph 6.5 ) partitioning experiments : octanol - buffer partitioning studies were 
 performed using a shake flask method as recommended by the organization for economic cooperation and 
 development ( oecd ) . before partitioning , the two solvents were 
 mutually saturated at 25c for 24 hr . solutions of the three sulfonamides ( 10 
 g / ml ) were prepared in the octanol - saturated buffer . these solutions were 
 then equilibrated at 25c with an equivalent , double and half volume of buffer - saturated octanol . equilibration was achieved by hand shaking of the funnels ( by 
 rotation of the funnels through 180 degrees about its transverse axis approximately one hundred times in five 
 min ) allowing the trapped air to rise through the two phases . the funnels were then fixed vertically by 
 racking until complete separation of the two phases . the buffer phase was collected and centrifuged at 1,600 
 g for 10 min at 25c , and the supernatant octanol phase the drug 
 concentration in the buffer phase was then determined by hplc , while that in the octanol phase was calculated 
 from the difference between the initial and final concentrations in the buffer phase . sdd , sdz and sa concentrations were determined in plasma , rumen juice and buffer samples by hplc with uv 
 detection . two hundred microliters of perchloric acid ( 0.5 m ) was added to 200 l of the 
 plasma sample . the mixture was vortexed for 30 sec and then centrifuged at 20,000 g for 10 
 min at 5c . fifty 
 microliters of the filtrate was injected into the hplc column . in the case of rumen juice samples , sdd , sdz and sa concentrations were determined after extraction with 
 ethyl acetate . after being incubated for 24 hr , 50 l of the internal standard ( 200 
 g / ml ) was added to the rumen juice samples . the internal standards used 
 in the present study were sulfadimethoxine , sa and sdz for sdd , sdz and sa , respectively . the mixtures were vortexed for 30 sec and then centrifuged at 
 3,000 g for 10 min at 5c . the obtained supernatants were transferred into pear - shaped flasks 
 and evaporated to dryness at 30c . the residue was reconstituted in 500 l of the mobile 
 phase and filtered using the 0.45-m hplc filter . the mobile phases used were a mixture of 50 mm acetate buffer ( ph 5 ) and acetonitrile ( 75:25 , v / v ) for sdd , a 
 mixture of 50 mm acetate buffer ( ph 4 ) and acetonitrile ( 75:25 , v / v ) for sdz , and a mixture of 50 mm acetate 
 buffer ( ph 5 ) and acetonitrile ( 80:20 , v / v ) for sa . analytical separation was accomplished using a 
 reversed - phase c8 column ( mightysil rp-8 gp , 4.6 m  250 mm , kanto chemical co. , 
 tokyo , japan ) . the recoveries of sdd , sdz and sa from plasma samples at 1 g / ml ( n=5 ) were 
 109.2  2.00% , 87.9  1.52% and 95.0  1.75% , while those from rumen juice samples at 10 
 g / ml ( n=5 ) were 83.5  2.06% , 84.3  2.09% and 88.1  2.35% , 
 respectively . the inter - day cv values for plasma samples ranged from 1.67 to 2.14% for sdd , 0.63 to 3.84% for 
 sdz and from 1.21 to 2.29% for sa , while those for rumen juice samples ranged from 1.86 to 2.79% for sdd , 1.96 
 to 5.24% for sdz and 1.61 to 3.57% for sa ( n=5 , 3 times ) . differences in the mean values between groups were analyzed by 
 scheff s multiple comparison test after a one - way anova single factor test . the plasma concentration - time curves of sdd , sdz and sa after their intravenous administration fit well with 
 the one compartment model . therefore , the curves obtained after the intravenous injections 
 ( cpiv ( t ) ) and those after their oral administration 
 ( cppo ( t ) ) were described by eqs . 1 and 2 , respectively . equations 1 and 2 were simultaneously fit to the plasma concentration - time curves after the intravenous 
 injections and oral administration to the same goats , respectively , in order to calculate pharmacokinetic 
 parameters by the nonlinear least - squares method using the curve fitting program , multi . the area under the 
 concentration versus time curve ( auc ) was calculated by the trapezoidal method ( from time zero to the last 
 sampling time ) and integration ( from the last sampling time to infinity ) . total body clearance 
 ( cltot ) , bioavailability ( f ) , mean residence time ( mrt ) , mean absorption time ( mat ) , elimination 
 half - life ( t1/2kel ) and distribution volume at a steady state ( vdss ) the plasma concentrations against time curves obtained after a single intravenous or oral dosing of sdd , sdz or 
 sa are shown in fig . 1fig . 1.plasma concentration - time curves of a ) sulfadimidine ( sdd ) , b ) sulfadiazine ( sdz ) and c ) sulfanilamide 
 ( sa ) after their single intravenous ( opened circles ) and oral administration ( closed circles ) to shiba 
 goats at a dose of 10 mg / kg body weight . each point and vertical bar represent the mean and standard 
 deviation , respectively ( n=5 ) . each line was calculated by eq . 1 or 2 using the pharmacokinetic parameters 
 in table 1 .. the plasma concentrations of sdd , sdz and sa rapidly increased and peaked at 2.0 , 6.0 and 7.8 hr ( table 1table 1.pharmacokinetic parameters of sulfadimidine , sulfadiazine and sulfanilamide in shiba goats 
 ( n=5 ) after their intravenous and oral administration at 10 mg / kg body weight parameterunitsulfadimidinesulfadiazinesulfanilamidekahr0.136  0.017 0.064  0.0060.097  0.023t1/2kahr5.17  0.66310.9  1.087.46  1.70kelhr0.728  0.3570.454  0.0730.188  0.016t1/2kelhr1.09  0.3781.56  0.2743.71  0.340cmaxg / ml2.14  1.052.70  0.5682.08  0.379tmaxhr2.00  1.236.00  0.007.80  1.64f%41.6  14.979.8  13.048.1  1.79f*%44.9  16.483.9  17.049.2  2.11mathr7.52  0.85013.2  2.029.09  1.67mrti.v.hr1.61  0.5642.13  0.3375.33  0.396mrtp.o.hr9.13  1.0215.3  1.9314.4  1.98auc i.v.ghr/ml55.2  31.355.0  4.7481.3  19.9auc p.o.ghr/ml22.5  13.346.0  9.1839.8  8.95cll a ) significantly different from sulfadimidine , b ) significantly 
 different from sulfadiazine , c ) significantly different from sulfanilamide . ka = absorption rate constant ; t 
 1/2ka = half - life of absorption ; kel = elimination rate constant ; 
 t1/2kel = half - life of elimination ; cmax = maximum plasma concentration ; 
 tmax = time to maximum plasma concentration ; f = bioavailability calculated by a compartmental 
 analysis ; f*=bioavailability calculated by a non - compartmental analysis ; mat = apparent mean absorption 
 time ; mrti.v.=mean residence time after an i.v . injection ; mrtp.o.=mean residence 
 time after p.o . injection ; aucp.o.=area under the plasma concentration  time curve after oral 
 administration ; cl = total body clearance ; vdss = volume of distribution at a steady state . ) , respectively , after their oral administration , and this was followed by their slow elimination . 
 on the other hand , their plasma concentrations decreased rapidly after the intravenous injections with markedly 
 shorter half - lives ( table 1 ) , indicating a flip - flop phenomenon 
 after the oral administration of the three drugs . plasma concentration - time curves of a ) sulfadimidine ( sdd ) , b ) sulfadiazine ( sdz ) and c ) sulfanilamide 
 ( sa ) after their single intravenous ( opened circles ) and oral administration ( closed circles ) to shiba 
 goats at a dose of 10 mg / kg body weight . each point and vertical bar represent the mean and standard 
 deviation , respectively ( n=5 ) . each line was calculated by eq . 1 or 2 using the pharmacokinetic parameters 
 in table 1 . a ) significantly different from sulfadimidine , b ) significantly 
 different from sulfadiazine , c ) significantly different from sulfanilamide . ka = absorption rate constant ; t 
 1/2ka = half - life of absorption ; kel = elimination rate constant ; 
 t1/2kel = half - life of elimination ; cmax = maximum plasma concentration ; 
 tmax = time to maximum plasma concentration ; f = bioavailability calculated by a compartmental 
 analysis ; f*=bioavailability calculated by a non - compartmental analysis ; mat = apparent mean absorption 
 time ; mrti.v.=mean residence time after an i.v . injection ; aucp.o.=area under the plasma concentration  time curve after oral 
 administration ; cl = total body clearance ; vdss = volume of distribution at a steady state . as shown in table 1 , a pharmacokinetic analysis revealed the 
 different absorption profiles of the three sulfonamides in shiba goats after their oral administration . the mat 
 and t1/2ka of sdz were significantly longer than those of sdd and sa . the order of mat values was 
 different from that of the unionized fraction at ph 6.5 ( sa > sdd > sdz , see table 2table 2.physicochemical parameters and mat of sulfadimidine , sulfadiazine and sulfanilamidesulfonamidespka ( fu)pp*mat ( hr)sulfadimidine7.5 ( 90%)1.96  0.1622.167.52  0.85sulfadiazine6.5 ( 50%)0.468  0.0490.93513.2  2.02sulfanilamide10.5 ( 99.9%)0.257  0.0470.2579.09  1.67fu : unionized fractions ( calculated at ph 6.5 ) , pka : referred from references 8 and 13 , 
 p : partition coefficient between octanol and phosphate buffer at ph 6.5 , 
 p * : intrinsic partition coefficient calculated from the apparent partition coefficient 
 and pka in the table , mat : mean absorption time in the present study . ) and was also different from that of partition coefficients at ph 6.5 ( sdd > sdz > sa , see 
 table 2 ) . the oral bioavailabilities of sdd and sa were less than 
 50% and lower than that of sdz . fu : unionized fractions ( calculated at ph 6.5 ) , pka : referred from references 8 and 13 , 
 p : partition coefficient between octanol and phosphate buffer at ph 6.5 , 
 p * : intrinsic partition coefficient calculated from the apparent partition coefficient 
 and pka in the table , mat : mean absorption time in the present study . the recovery of sulfonamides from rumen juice samples after a 24-hr incubation was 88.6  4.61% for sdd , 89.9  
 3.61% for sdz and 76.5  4.85% for sa . these values were markedly higher than those for bioavailability , 
 suggesting that sdd and sa were exposed to the extensive  first - pass effect of the liver . oral drug absorption is generally more complex and unpredictable in ruminants and may exhibit markedly 
 different kinetics from those in monogastric species , and these differences have been attributed to the unique 
 anatomical and physiological features of the gastrointestinal tract in ruminants . the forestomach ( rumen , 
 reticulum and omasum ) is a large volume compartment ( 100225 l in cattle and 1024 
 l in sheep and goats ) , which may result in the dilution and long residence time of drugs in 
 the forestomach . furthermore , the inner structure of the forestomach 
 is lined by a keratinized stratified squamous epithelium , which may also contribute to the slow absorption of 
 drugs . we previously reported the marked absorption of diclofenac from the forestomach of shiba goats after its 
 oral administration and suggested that this may have been due to the high lipid solubility of the drug . therefore , we herein examined the absorption profiles of sdd , sdz and sa , 
 which have different pka , but similar lipophilicities ( table 2 ) 
 after their oral administration to shiba goats . the absorption rate 
 of sdz from the forestomach of goats may have been markedly slower , because of its longer mat and 
 t1/2ka than those of sdd and sa . the pka values of sdz , sdd and sa were previously reported to be 
 6.5 , 7.5 and 10.5 , respectively [ 8 , 13 ] , suggesting that 50% of sdz molecules are unionized , sdd molecules mainly exist in an unionized 
 form ( 90% ) , and sa molecules are mainly unionized ( more than 99.9% ) in the rumen juice because its ph value was 
 6.5 in this study , as has been reported previously [ 3 , 6 ] . therefore , the slow absorption rate of sdz from the forestomach may have 
 been due to its lower degree of unionization than sdd and sa in the rumen juice . a comparison of the mat of sdd in the present study with that of smm in our previous study on shiba goats 
  revealed that the mat of sdd ( 7.52  0.85 hr ) was less than half 
 that of smm ( 15.1  4.7 hr ) , whereas the partition coefficients of octanol and the buffer ( ph=6.5 ) were nearly 
 similar ; that of sdd was 1.96  0.16 ( table 2 ) , and that of smm was 
 1.72  0.17 ( determined by the method used in the present study ) . however , the percentage of the unionized 
 fraction in the rumen juice ( ph 6.5 ) was different ( approximately 90% for sdd and 30% for smm ) . therefore , sdd 
 may have been absorbed more from the forestomach than smm , because of its markedly higher unionization in the 
 rumen juice , suggesting that drugs with high unionization are largely absorbed from the forestomach of 
 ruminants . no significant differences were observed in the mat between sdd and sa ( table 1 ) , and may have been because of the nearly similar degree of unionization of both drugs in the 
 forestomach ( table 2 ) . therefore , the degree of unionization may be 
 an important factor for the absorption of drugs from the forestomach after their oral administration . the plasma concentration curves of three sulfonamides shown in fig.1 
 revealed at the flip - flop phenomena . these flip - flop kinetics occur when the absorption rate constant ( ka ) is 
 smaller than the elimination rate constant ( kel ) , and therefore , the slope of the terminal log - linear 
 phase after oral administration of a drug reflects the absorption rate constant . as listed in table 1 , ka values of three drugs were smaller than kel 
 values in the same way . when oral pharmacokinetics exhibits flip - flop phenomena , the determining factor of 
 tmax is function of the drug elimination results in the shorter tmax . the elimination 
 half - life ( 1.09 hr ) of sdd was shorter than half - lives ( 1.56 and 3.71 hr ) of other two drugs ( sdz and 
 sa).therefore , the elimination of sdd in shiba goat may have been fast enough to acheve cmax more 
 rapidly ( 2.00 hr of tmax ) than sdz or sa after their oral administration . the slow absorption kinetics of three sulfonamides after their oral administration to male shiba goats were 
 shown in this study . the obtained 
 ka values ( 0.498 hr in pigs ) were markedly higher than those obtained from the shiba 
 goats in the present study ( 0.136 hr ) . the slow absorption rate of sulfanomaides in the shiba goats 
 may be due to their long residence time in the forestomach . we suggested that the lower bioavailability ( 44.9% as f * ) of sdd after oral administration was mainly due to 
 the considerable  first - pass effect in the liver because of its fast elimination rate ( 0.728 hr as 
 kel ) . the oral bioavailability of sdd was low ( 26.4% ) in dwarf goats and attributed this to a 
 consequence of the marked hepatic  first - pass effect as reported previously . it was also found that the oral bioavailability of a sdd solution was low ( 58.3% ) in sheep . another study also suggested that the low bioavailability of 
 sulfamethoxazole after its oral administration to goats was most likely due to the hepatic  first - pass effect 
 . on the other hand , although the slow elimination of sa ( 0.188 
 hr ) could nt explain the low oral bioavailability , the low stability ( 76.5% ) of sa in rumen juice 
 might explain the low bioavailavility of sa after its oral administration . these findings may support our 
 suggestion regarding the incomplete bioavailability of sdd and sa in the present study . in conclusion , the results of the present study suggest that drugs that are highly unionized in rumen juice as 
 well as highly lipophilic may be mainly absorbed from the forestomach of goats , indicating that an oral route is 
 suitable for such drugs , even in ruminants .
the oral pharmacokinetics of three sulfonamides , sulfadimidine ( pka 7.5 ) , sulfadiazine ( pka 6.5 ) and 
 sulfanilamide ( pka 10.5 ) , with different rates of unionization in rumen juice , were compared in shiba goats to 
 clarify the relationship between drug absorption profiles after their oral administration as well as their 
 degree of unionization in the rumen . 
 sulfonamides were administered either into the left jugular vein or 
 orally to five male goats at doses of 10 mg / kg body weight , using a crossover design with at least a 3-week 
 washout period . 
 the tmax of sulfadimidine , sulfadiazine and sulfanilamide reached 2.0  1.2 , 6.0  
 0.0 , and 7.8  1.6 hr , respectively , after their oral administration , and this was followed by their slow 
 elimination due to a slow rate of drug absorption from the gastrointestinal tract . 
 the mat and 
 t1/2ka of sulfadiazine ( 13.2  2.0 and 10.9  1.08 hr ) were significantly longer than those of 
 sulfanilamide ( 9.09  1.67 and 7.46  1.70 hr ) and sulfadimidine ( 7.52  0.85 and 5.17  0.66 hr ) . 
 these 
 results suggest that the absorption rates of highly unionized drugs ( such as sulfanilamide and sulfadimidine ) 
 from the forestomach of goats may be markedly higher than less unionized ones ( such as sulfadiazine ) . 
 the mean 
 oral bioavailability of sulfadiazine was high ( 83.9  17.0% ) , whereas those of sulfadimidine and sulfanilamide 
 were low ( 44.9  16.4% and 49.2  2.11% , respectively ) .