4. Chapter Two: Evaluation of Gastric Emptying Profiles of Shiba Goats by Oral
5.4. Results
- 55 - ܥሺݐሻ ൌ௦ήி
ೌ
ೌିሺ݁ିή௧െ ݁ିೌή௧ሻ (Eq. 2)
In Eq. 2, F is bioavailability. Equation 1and 2 were simultaneously fit to the plasma concentration-time curves after the intravenous injection 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 (72).
Several pharmacokinetic parameters were calculated by non-compartmental analysis. 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, mean residence time (MRT), mean absorption time (MAT), elimination half-life (t 1/2kel), peak plasma drug concentration (Cmax), time of occurrence of Cmax (Tmax), and the distribution volume at a steady state (Vdss) were calculated by conventional methods.
- 56 -
As shown in Table 3-1, the pharmacokinetic analysis indicated the slow absorption of the three sulfonamides in Shiba goats after intraruminal administration. The calculated MAT and absorption half-life (t1/2ka) of the three sulfonamides were long. The MAT of SDZ was significantly longer than that of SMZ and SA. The t1/2ka of SDZ was also significantly longer than that of SMZ and SA. The order of MAT values was different from that of pKa and therefore that of unionized fraction pH 6.5 (SA > S MZ > SDZ, see Table 3-2). It was also different from that of partition coefficient values at pH 6.5 (SMZ
> SDZ > SA, see Table 3-2). Oral bioavailabilities of SMZ and SA were found to be significantly lower than that of SDZ.
The recovery of sulfonamides from rumen juice samples after a 24-h incubation was 88.6 ± 4.61% for SMZ, 89.9 ± 3.61% for SDZ and 76.5 ± 4.85% for SA. These values were quite higher than bioavailability, suggesting that the low bioavailability of SMZ and SA was mainly due to the extensive first-pass effect in liver.
5.5. DISSCUSSION AND CONCLUSION
The oral drug absorption in ruminants is generally more complex, unpredictable and may exhibit a markedly different kinetics when compared with those in monogastric species. This may be due to the unique anatomical and physiological features of the gastrointestinal tract. The forestomach (rumen, reticulum, and omasum) is a large volume compartment (100~225 l in cattle, and 10~24 l in sheep and goats). This may result in the dilution of drugs and a long residence time in the forestomach (5). In addition, the inner structure of the forestomach is lined by a keratinized stratified squamous epithelium,
- 57 -
which may also contribute to slow drug absorption. In Chapter one, however, I indicated substantial absorption of diclofenac from forestmach after oral administration to Shiba goats. I also suggested that this may be due to high lipid solubility of the drug. In the present study, therefore, the absorption profiles of SMZ, SDZ and SA which have different lipophylicity and pKa (Table 3-2) were examined after their intraruminal administration to Shiba goats.
Marked differences were observed in the oral absorption profiles of the 3 sulfonamides. The MAT of SDZ (13.2 ± 2.02 h) was significantly longer than that of SA (9.09 ± 1.67 h) and SMZ (7.52 ± 0.850 h). In addition, the t1/2ka of SDZ (10.9 ± 1.08 h) was significantly longer than those of SA (7.46 ± 1.70 h) and SMZ (5.17 ± 0.663 h).
These results suggest that absorption of SDZ from the forestomach of goats may have been markedly slower than that of SMZ and SA. The pH value of the rumen juice in the present study was 6.5, as has been reported previously (18, 27). Considering rumen physiology versus the physicochemical properties of SMZ, SDZ and SA, it is possible that more absorption for SMZ did occur within this gastric compartment compared to SDZ and SA. The pKa values of SMZ, SDZ and SA are 7.5, 6.5 and 10.5, respectively (41, 66) suggesting that the SMZ molecules exist mainly as an unionized form (90%), SDZ molecules exist as 50% unionized and SA molecules exist mainly as unionized form (more than 99.9%), in the contents of the rumen. Therefore, SA is more suitable for absorption from the forestomach of goats compared to SMZ and SDZ because of its extreme unionization. However, the obtained partition coefficient between octanol and buffer (pH 6.5) in the present study was different. That of SMZ is 1.96, approximately four times like that of SDZ (0.47) and eight times like that of SA (0.26). Therefore, SMZ
- 58 -
may have been more absorbed from the forestomach than SDZ and SA because of its relatively higher lipid solubility and high unionization. The absorption rate of SA is larger than that of SDZ although the partition coefficient of SDZ is relatively higher than that of SA. A smaller molecular weight of SA (Table 3-2) may be considered to be one of the reasons reflecting the small lipophylicity and a rapid diffusion of SA through the gastrointestinal membranes (42). A similar unusually rapid urinary excretion was reported (73). Since the drugs are absorbed mainly and rapidly from the small intestines and gastric emptying is the determining factor for drug absorption after the oral administration of drugs (23, 27). Therefore, the slow absorption of three sulfonamides in goats in the present study may be due to their long residence time in the forestomach. Markedly higher ka values were obtained for SMM in pigs after its intraduodenal administration than after their oral administration (31).
In Chapter one, I have suggested the absorption of DF from the forestomach of Shiba goats (20). The MAT, t1/2ka and ka of DF was 6 h, 4.13 h and 0.19-h, respectively.
This indicates that DF was substantially absorbed from the forestomach because of its extremely higher lipid solubility although it exists mainly in the ionized form. The logarithm of the partition coefficient of the unionized form of DF at pH 6.6 is 4.34 (64), extremely higher than those of the three sulfonamides in the present study. Therefore, lipid solubility together with unionization may be an important factors for absorption of drugs from the forestomach of ruminants.
In the result section I suggested that, the lower bioavailabilities of SMZ and SA after intraruminal administration are mainly due to a considerable first-pass effect in the
- 59 -
liver. This is further supported the stability of both drugs in the rumen juice in the in vitro spiked test in the present study. Based on their chemical structures, most sulphonamides are unlikely to undergo biodegradation in the rumen juice. Negligible biodegradations of sulphamethoxydiazine, sulphathiazole and sulphamoxole in ruminal fluid of the dwarf goats during anaerobic incubation at 39°C were found (68). A previous study also suggested that the low bioavailability of sulphamethoxazole after its oral administration to goats was most likely due to the first-pass effect in the liver (51). In goats, the systemic bioavailability was 20, 11.4 and 23.3% after oral administration of sulphamethoxazole, sulphadimethyloxazole and sulphadimethoxine, respectively (3). In dwarf goats, the oral bioavailability of SMZ is low (26.4%), probably as a consequence of a marked first-pass effect in the liver (67, 70). These findings support our suggestion about the incomplete bioavailability of the three sulfonamides in the present study.
In conclusion, the results of the present study suggest that, drugs that have appropriate physicochemical properties such as high lipid solubility, good unionization and a small molecular weight may be markedly absorbed from the forestmach of goats.
A possibility raises that oral route may be suitable for such drugs, even in goats.
- 60 - Fig. 3-1.
Plasma concentration-time curves of SMZ (10 mg/kg bodyweight) after its single intravenous (open circles) and intraruminal administration (closed circles) to male Shiba goats. Each point and vertical bar represents the mean and standard deviation, respectively (n = 5). Each line is calculated by Eq. 1 or 2 using pharmacokinetic parameters in Table 3-1.
0.01 0.1 1 10 100
0 4 8 12 16 20 24
Plasma concentration (ug/ml)
Time after administration (h)
- 61 - Fig. 3-2.
Plasma concentration-time curves of SDZ (10 mg/kg bodyweight) after its single intravenous (open circles) and intraruminal administration (closed circles) to male Shiba goats. Each point and vertical bar represents the mean and standard deviation, respectively (n = 5). Each line is calculated by Eq. 1 or 2 using pharmacokinetic parameters in Table 3-1.
0.01 0.1 1 10 100
0 6 12 18 24 30 36 42 48
Plasma concentration (μg/ml)
Time after administration (h)
- 62 - Fig. 3-3.
Plasma concentration-time curves of SA (10 mg/kg bodyweight) after its single intravenous (open circles) and intraruminal administration (closed circles) to male Shiba goats. Each point and vertical bar represents the mean and standard deviation, respectively (n = 5). Each line is calculated by Eq. 1 or 2 using pharmacokinetic parameters in Table 3-1.
0.01 0.1 1 10 100
0 6 12 18 24 30 36 42 48
Plasma concentration (μg/ml)
Time after administration (h)
- 63 - Table 3-1.
Pharmacokinetic parameters of SMZ, SDZ and SA in male Shiba goats (n = 5) determined after a single intravenous and intraruminal administration of 10 mg/kg
bodyweight.
SMZ SDZ SA
Parameter Units Mean ± SD Mean ± SD Mean ± SD
ka h-1 0.136 ± 0.017bc 0.0639 ± 0.0062a 0.0971 ± 0.0229a Cmax μg/ml 2.14 ± 1.05 2.70 ± 0.57 2.08 ± 0.38
Tmax h 2.00 ± 1.23 6.00 ± 0.00 7.80 ± 1.64
kel h-1 0.728 ± 0.357 0.454 ± 0.073 0.188 ± 0.016
t1/2ka h 5.17 ± 0.66b 10.9 ± 1.1ac 7.46 ± 1.70b
t1/2kel h 1.09 ± 0.38 1.56 ± 0.27 3.71 ± 0.34
AUCi.v. μgh/ml 55.2 ± 31.3 55.0 ± 4.7 81.3 ± 19.9
AUCp.o. μgh/ml 22.5 ± 13.3 46.0 ± 9.2 39.8 ± 9.0 CL l/h/kg 0.311 ± 0.329 0.183 ± 0.016 0.129 ± 0.031
F % 41.6 ± 14.9 79.8 ± 13.0 48.1 ± 1.8
F* % 44.9 ± 16.4 83.9 ± 17.0 49.2 ± 2.1
MRTi.v. h 1.61 ± 0.56 2.13 ± 0.34 5.33 ± 0.40
MRTp.o. h 9.13 ± 1.02 15.3 ± 1.9 14.4 ± 2.0
MAT h 7.52 ± 0.85b 13.2 ± 2.0ac 9.09 ± 1.67b
Vdss l/kg 0.374 ± 0.207 0.386 ± 0.033 0.683 ± 0.144
a: means presence of a significant difference from SMZ.
b:means presence of a significant difference from SDZ.
c:means presence of a significant difference from SA.
ka = absorption rate constant; Cmax = maximum plasma concentration; Tmax = time to maximum plasma concentration; kel = elimination rate constant; t1/2ka = half-life of absorption; t1/2kel = half-life of elimination; AUCi.v. = area under the plasma concentration–time curve from time zero to infinity after i.v. injection; AUCp.o. = area under the plasma concentration–time curve from time zero to infinity after intraruminal administration; CL = total body clearance; F = bioavailability calculated by compartmental analysis; F* = bioavailability calculated by non-compartmental analysis; MAT* = real mean absorption time; MRTi.v. = mean residence time after i.v. injection;
MRTp.o. = mean residence time after p.o administration; MAT = apparent mean absorption time;
Vdss = volume of distribution at a steady state.
- 64 - Table 3-2.
Some physicochemical parameters and MAT of SMZ, SDZ and SA.
Sulfonamides Chemical structure pKa
(fu%) P P* Molecular weight MAT (h)
SMZ C12H14N4O2S 7.5 (66)
(90) 1.96 ± 0.16 2.16 ± 0.18 278.3 7.52 ± 0.85
SDZ C10H10N4O2S 6.5 (66)
(50) 0.468 ± 0.049 0.935 ± 0.098 272.3 13.2 ± 2.0
SA C6H8N2O2S 10.5 (41)
(100) 0.257 ± 0.047 0.257 ± 0.047 172.2 9.09 ± 1.67
fu: Unionized fractions (calculated at pH 6.5).
P: octano/phosphate buffer (50 mM, pH 6.5) apparent partition coefficient in the present study at 25°C.
P*: octano/phosphate buffer (50 mM, pH 6.5) intrinsic partition coefficient in the present study at 25°C.
MAT: mean absorption time in the present study.
- 65 -
- 66 -
Oral ingestion of drugs is considered one of the main routes of drug administration due to convenience, easy treatment of large number of animals, absence of stress and avoiding both tissues damage and local residues after injection.
Differences in the anatomy and physiology of the gastrointestinal tract between human and animals also among animals results in major species differences in strategies for and efficiency of oral drug administration (54). In ruminants, the forestomach (rumen, reticulum, and omasum) is a large volume compartment (100~225 l in cattle, and 10~24 l in sheep and goats) resulting in dilution of drugs and a long residence time in the forestomach (5). In addition, the keratinized stratified squamous epithelium lining the forestomach may also contribute to slow drug absorption. Moreover, microflora in the rumen may inactivate some drugs through metabolic or chemical reactions (6). All of these makes the oral drug absorption in ruminants more complex and unpredictable and exhibiting markedly different kinetics when compared with those of simple stomach animals.
Although the main absorption site of drugs after oral dosing is the small intestine, the absorption of some drugs from the stomach may also be markedly high. This has been demonstrated for salicylic acid (17), sulfaethidole and barbital (11) and metoprolol (18) in rats. This has been demonstrated also for sulfonamides (4), salicylate, pentobarbitone, quinine (28) and thiabendazole (38) in ruminants. Absorption of drugs from stomach shortens the MAT of drugs.
Since the effective surface area of the stomach that actually contributes to drug absorption is small, the physicochemical properties of drugs such as pKa, lipophilicity, solubility, stability in the gastrointestinal fluids and molecular size may be important factors for their absorption from the stomach (75).
- 67 -
In this thesis, I aimed to clarify the correlations between drugs absorption profiles after oral administration to ruminants and their physicochemical properties. To achieve this, several drugs with different physicochemical properties (Table 4-2) were chosen.
Followings are the investigations and major outcomes of the present research.
6.1. Oral pharmacokinetics of the acidic drugs, diclofenac and sulfamonomethoxine in Shiba goats.
This study is presented in Chapter one, in which the oral absorption profiles of DF and SMM were investigated in Shiba goats, a small ruminant animal to evaluate the correlation of their absorption parameters with their physicochemical properties. The results of a pharmacokinetic analysis revealed the slow absorption of both drugs. A marked difference was observed in the oral absorption profiles of DF and SMM. The MAT of DF (6.05 ± 2.74 h) was less than half that of SMM (15.1 ± 4.70 h) in the present study. The t1/2ka
of DF (4.13 ± 1.94 h) is also less than half that of SMM (10.5 ± 3.60 h) as shown in Table 4-1. These results suggests that absorption rate of DF from the forestomach of male Shiba goats may have been markedly higher than that of SMM because of its extremely higher lipophylicity (Table 4-2). The t1/2ka values were also longer than that of those reported in human and simple stomach animals like horses, pigs, rabbits and rats suggesting the long residence time in the forestomach. These results may indicate that absorption of highly lipophilic drugs from the forestomach may be markedly high in ruminants and the gastric emptying may be the determining factor for drug absorption after the oral administration of drugs to Shiba goats.
- 68 -
6.2. Evaluation of gastric emptying profiles of Shiba goats by oral pharmacokinetics of acetaminophen.
This study is presented in Chapter two, in which the pharmacokinetics of acetaminophen after oral dosing to Shiba goats were examined in order to evaluate the property of gastric emptying. The obtained MAT and t1/2ka were unexpectedly short (4.93 ± 0.867 and 3.35 ± 0.501 h, respectively) as shown in Table 4-1 due to its relatively low lipophylicity when compared with DF (Table 4-2). These results suggests that AAP was markedly absorbed from the forestomach of male Shiba goats and this may be due to its smaller molecular weight and extreme unionization throughout the gastrointestinal tract (Table 4-2). This result may indicate that AAP was considered not suitable for the evaluation of the gastric emptying in in Shiba goats although it is generally considered as a good indicator of the gastric emptying in several animal species. These results may also indicate that acidic drugs having small molecular weight and high pKa (more than 8) may be markedly absorbed from the forestomach of ruminants, like AAP, even if they have relatively low lipid solubility. It was observed that oral bioavailability of AAP was extremely low (16.0 ± 8.52%) while the drug was stable in rumen juice for 24 h at 39°C suggesting its extensive first-pass effect in the liver. This result may indicate that AAP cannot be used as analgesic antipyretic in Shiba goats.
- 69 -
6.3. Oral absorption profiles of sulfonamides in Shiba goats: a comparison among sulfamethazine, sulfadiazine, and sulfanilamide.
This study is presented in Chapter three, in which the pharmacokinetics of sulfamethazine, sulfadiazine, and sulfanilamide after intraruminal administration to Shiba goats were examined in order to clarify the relationship between drug absorption profiles after their oral administration to ruminants and their physicochemical properties. As shown in Table 4-1, a pharmacokinetic analysis indicated the slow absorption of the three sulfonamides after intraruminal administration. The obtained MAT and t1/2ka of the three sulfonamides were long. Marked differences were observed in the oral absorption profiles of the 3 sulfonamides. The MAT of SDZ (13.2 ± 2.02 h) was significantly longer than that of SA (9.09 ± 1.67 h) and SMZ (7.52 ± 0.850 h). In addition, the t1/2ka of SDZ (10.9 ± 1.08 h) was significantly longer than those of SA (7.46 ± 1.70 h) and SMZ (5.17 ± 0.663 h). These results suggest that absorption of SDZ from the forestomach of goats may have been markedly slower than that of SMZ and SA. This may have been due to difference of the partition coefficient between octanol and buffer (pH 6.5) of the three sulfonamides. That of SMZ is 1.96 ± 0.126, approximately four times like that of SDZ (0.468 ± 0.049) and eight times like that of SA (0.257 ± 0.047). Therefore, SMZ may have been more absorbed from the forestomach than SDZ and SA because of its relatively higher lipid solubility and high unionization. These results indicate that the absorption rate of sulfonamides from forestomach of ruminants depend mainly on their degree of lipid solubility. Comparing the absorption profiles of SA and SDZ, SA had unexpectedly shorter MAT and t1/2ka than SDZ although the partition coefficient of SDZ is nearly twice that of SA. A smaller molecular weight of SA (Table 4-2) may be considered to be one of the reasons reflecting the small
- 70 -
lipophylicity and a rapid diffusion of SA through the gastrointestinal membranes. The extreme unionization of SA throughout the gastrointestinal tract due to high pKa may be another reason. Therefore, it is indicated that drugs with small molecular weight and high unionization may be markedly absorbed from the forestomach of ruminants, even though they have a low degree of lipid solubility. Comparing the absorption profiles of SA and AAP it was found that AAP was more absorbed from the forestomach of Shiba goats than SA.
MAT and t1/2ka of AAP were shorter than those of SA (Table 4-1). This may have been due to the higher lipid solubility and small molecular weight of AAP. The partition coefficient of AAP at pH 6.5 was approximately 8 times like that of SA. Also the smaller molecular weight of the AAP may be considered also as another reason (Table 4-2).
As shown in Table 4-2, SA and AAP have high pKa, extremely unionized at pH 6.5 and small molecular weights and the apparent and intrinsic partition coefficient of each drug are same.
In conclusion, the appropriate physicochemical properties of drugs such as high lipid solubility, good unionization and a small molecular weight may be an important factors for drug absorption from the forestmach of goats. It is, therefore, suggested a possibility that oral route may be suitable for such drugs, even in ruminants.
- 71 - Table 4-1.
Mean pharmacokinetic parameters parameters ± SD (n = 5) of sulfamethazine (SMZ), sulfadiazine (SDZ), sulfanilamide (SA), sulfamonomethoxine (SMM), diclofenac (DF) and acetaminophen (AAP).
Drug SMZ SDZ SA SMM DF AAP
D/V (mg/l) 31.2 10.1 23.5 2.8 14.5 2.9 33.3 8.33 14.9 7.4 68.8 32.0 V (l/kg) 0.355 0.139 0.430 0.052 0.711 0.133 0.307 0.112 - - - -
kel (h-1) 0.728 0.357 0.454 0.073 0.188 0.016 0.703 0.084 - - - -
F comp (%) 0.416 0.149 0.798 0.130 0.481 0.018 79.3 16.5 75.4 24.0 0.176 0.083
F'non comp (%) 0.449 0.164 0.839 0.170 0.492 0.021 77.1 14.8 73.9 20.2 0.160 0.085
AUCiv (μgh/ml) 55.2 31.3 55.0 4.7 81.3 19. 9 49.9 11.3 14.7 6.2 35.7 7.6
AUCpo (μgh/ml) 22.5 13.3 46.0 9.2 39.8 9.0 37.5 6.7 10.4 4.0 5.34 2.16
t1/2kel or t1/2β (h) 1.09 0.38 1.56 0.27 3.71 0.34 0.997 0.112 3.05 1.13 1.14 0.46
t1/2ka (h) 5.17 0.66 10.9 1.1 7.46 1.70 10.5 3.6 4.13 1.94 3.35 0.50
CL (l/h/kg) 0.311 0.329 0.183 0.016 0.129 0.031 0.212 0.067 0.0748 0.0309 0.869 0.163
MRTiv (h) 1.61 0.56 2.13 0.34 5.33 0.40 1.49 0.19 2.38 1.01 0.617 0.148
MRTPO (h) 9.13 1.02 15.3 1.9 14.4 2.0 16.6 4.6 8.42 2.15 5.46 0.86
Vdss (l/kg) 0.374 0.207 0.386 0.033 0.683 0.144 0.321 0.134 0.181 0.102 0.546 0.192 ka (h-1) 0.136 0.017 0.0639 0.0062 0.0971 0.0229 0.0737 0.0296 0.194 0.073 0.210 0.032 MAT (h) 7.52 0.85 13.2 2.0 9.09 1.67 15.1 4.7 6.05 2.74 4.93 0.87
Cmax (μg/ml) 2.14 1.05 2.70 0.57 2.08 0.38 2.15 0.29 1.12 0.58 0.985 0.453
tmax (h) 2.00 1.23 6.00 0.00 7.80 1.64 5.60 2.30 1.51 1.41 0.900 0.224
α (h-1) - - - 2.09 0.97 3.37 2.06
β (h-1) - - - 0.250 0.078 0.695 0.267
k21 (h-1) - - - 0.460 0.166 1.05 0.64
- 72 - Table 4-2.
Absorption profile and some physicochemical properties of SMZ, SDZ, SA, SMM, DF and AAP.
Drug SMZ SDZ SA SMM DF AAP
pKa 7.5 (66) 6.5 (66) 10.4 (41) 6 (46) 4 (53) 9.56 (40)
fu% 90 50 100 30 0.3 100
P 1.96 ± 0.13 0.468 ± 0.049 0.257 ± 0.047 1.72 ± 0.17 91.8 ± 9.5 2.07± 0.17
P* 2.16 ± 0.18 0.935 ± 0.098 0.257 ± 0.047 7.15 ± 0.86 29118.7 ± 2735.8 2.07 ± 0.17
Molecular weight 278. 3 272.3 172.2 303.3 318.1 151.2
MAT 7.52 ± 0.85 13.2 ± 2.0 9.09 ± 1.67 15.1 ± 4.7 6.05 ± 2.74 4.93 ± 0.87
ka 0.136 ± 0.017 0.0639 ± 0.0062 0.0971 ± 0.0229 0.0737 ± 0.0296 0.19 ± 0.07 0.210 ± 0.032
fu%: unionized fractions (calculated at pH 6.5).
pKa: dissociation constants, referred from (40, 41, 46, 53, 66).
P: octano/phosphate buffer (50 mM, pH 6.5) apparent partition coefficient in the present study at 25°C.
P*: octano/phosphate buffer (50 mM, pH 6.5) intrinsic partition coefficient in the present study at 25°C.
MAT: mean absorption time in the present study.
ka: absorption rate constant.
- 73 -
7. ACKNOWLEDGMENTS
First of all, I would to pray, thank and to express my deepest gratitude and indebtedness to the Glorious and theAlmighty ALLAH who gave me the ability and the strength to start and accomplish this work.
My cordial feeling of sincerety is due to my country (Egypt), which raisd me and gave me the chance and the financial support to study abroad.
I would like to express my deepest gratitude, cardial and sincere thanks to Prof.
Dr. Minoru Shimoda and Associate Prof. Dr. Kazuaki Sasaki, Laboratory of Pharmacology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology for their kind supervision, guidance, their moral support, continuous help, fruitful advices and encouragement during the entire course of this work. The author wishes to appreciate Dr. Mohamed Aboubakr, Mr. Takara Sakiyama, Mr. Yuji Miazaki, Mr. Yusuke Ishihara for their co-work, etc.
Many thanks to my Professors of Pharmacology at Faculty of Veterinary Medicine, Benha University, Egypt, Prof. Dr. Mossad G. A. Elsayed and Prof. Dr. Ashraf A. Elkomy for their teaching me, guidance, sharing of their knowledge and experiance with me and their contribution toward my academic carrier up to this level.
My deepest thanks to my parents whome supported and encouraged me a lot in my life and and during my study. I do appreciate and admire the kindness of my beloved wife and my kids, Kareem and Ziad for their patience and endurance during my study.
Words can not describe how much I appreciate what all of you did for me, but let me try thank you.
- 74 -
8. REFERENCES
1. el-Sayed, Y. M., Abdel-Hameed, M. E., Suleiman, M. S. and Najib, N. M. (1988).
A rapid and sensitive high-performance liquid chromatographic method for the determination of diclofenac sodium in serum and its use in pharmacokinetic studies.
J. Pharm. Pharmacol. 40, 727~729.
2. Ahmad, M., Iqbal, M. and Murtaza, G. (2012). Comparison of bioavailability and pharmacokinetics of diclofenac sodium and diclofenac potassium in normal and alloxan-diabetic rabbits. Pak. J. Pharm. Sci. 25, 301~306.
3. Atef, M., Youssef, S. A. H., Ramadan, A. and Issa, M. (1989). Kinetic disposition, systemic bioavailability, tissue levels and acetylation of some sulphonamides in goats. Arch. Int. Pharmacodyn. Ther. 302, 27~39.
4. Austin, F. H. (1967). Absorption, distribution and excretion of sulfonamides in ruminants. Fed. Proc. 26, 1001~1005.
5. Baggot, J. D. (1977). Principles of drug disposition in domestic animals. In: Baggot, J. D, [eds] The Basis of Veterinary Clinical Pharmacology, 1st ed., pp. 22~47. W.
B. Saunders Company, Philadelphia.
6. Baggot, J. D. and Brown, S. A. (1998). Basis for selection of the dosage form. In:
Hardee, G. E. and Baggot, J. D, [eds] Development and Formulation of Veterinary Dosage Forms, 2nd ed., pp. 7~143. Marcel Dekker, New York.
7. Bogan, J. A., Galbraith, A., Baxter, P., Ali, N. M. and Marriner, S. E. (1984). Effect of feeding on the fate of orally administered phenylbutazone, trimethoprim and sulphadiazine in the horse. Vet. Rec. 8, 599~600.
8. Bogan, J. A. and Marriner, S. E. (1987). The rumen as a pharmacokinetic
- 75 -
compartment. In: Ooms, L. A. A., Degryse, A. D. and van Miert, A. S. J. P. A. M.
[eds] Physiological and Pharmacological Aspects of the Reticulo-rumen, pp, 253~269. Martinus Nijhoff, Dordecht.
9. Carli, S., Sonzogni, O. and Villa, R. (1993). Pharmacokinetic profile of sulfamonomethoxine-trimethoprim in horses after intravenous, intramuscular and oral administration. Res. Vet. Sci. 54, 184~188.
10. Clements, J. A., Heading, R. C., Nimmo, W. S. and Prescott, L. F. (1978). Kinetics of acetaminophen absorption and gastric emptying in man. Clin. Pharmacol. Ther.
24, 420~431.
11. Crouthamel, W. C., Tan, G. H., Dittert, L. W. and Doluisio, J. T. (1971). Drug absorption IV: Influence of pH on absorption kinetics of weakly acidic drugs. J.
Pharm. Sci. 60, 1160~1163.
12. Davis, L. E. and Westfall, B. A. (1972). Species differences in biotransformation and excretion of salicylate. Am. J. Vet. Res. 33, 1253~1262.
13. Davis, N. M. and Anderson, K. E. (1997). Clinical pharmacokinetics of diclofenac.
Therapeutic insights and pitfalls. Clin. Pharmacokinet. 33, 184~213.
14. De Backer, P., Braeckman, R., Belpaire, F. and Debackere, M. (1980).
Bioavailability and pharmacokinetics of phenylbutazone in the cow. J. Vet.
Pharmacol. Therap. 3, 29~33.
15. DeGraw, R. T., Burleigh, J., Guinn, R. and Zhu, Y. (2008). Measuring first-pass metabolism using automated blood sampling. Poster presented at the Great Lakes Drug Metabolism Discussion Group in Indianapolis, Indiana. Poster retrieved from http://www.basinc.com/library/presentations/pdf/Tyler-01.pdf.
16. Doherty, T. J., Andrews, F. M., Provenza, M. K. and Frazier, D. L. (1998).
- 76 -
Acetaminophen as a marker of gastric emptying in ponies. Equine. Vet. J. 30, 349~351.
17. Doluisio, J. T., Billups, N. F., Dittert, L. W., Sugita, E. T. and Swin-tosky, J. V.
(1969). Drug absorption I: An in situ rat gut technique yielding realistic absorption rates. J. Pharm. Sci. 58, 1196~1200.
18. Domenech, J., Alba, M., Morera, J. M., Obach, R. and PlaDelfina, J. M. (1985).
Gastric, intestinal and colonic absorption of metoprolol in the rat. Br. J. Clin.
Pharmacol. 19, 85S~89S.
19. Domingue, B. M. F, Dellow, D. W. and Barry, T. N. (1991). Voluntary intake and rumen digestion of a low-quality roughage by goats and sheep. J. Agric. Sci. 17, 111~120.
20. Elbadawy, M., Sakiyama, T., Abohatab, R., Sasaki, K. and Shimoda, M. (2014).
Oral pharmacokinetics of the acidic drugs, diclofenac and sulfamonomethoxine in male Shiba goats. J. Vet. Med. Sci., http://dx.doi.org/10.1292/jvms.14-0261
21. Friend, D. (2004). Drug delivery to the small intestine. Curr. Gastroenterol. Rep. 6, 371~376.
22. Gibaldi, M. (1991). Gastrointestinal absorption-biological consideration. In:
Gibaldi, M. [eds] Biopharmaceutics and Clinical Pharmacokinetics, 4th ed., pp, 24~58. Lea and Lea Febiger, Philadelphia.
23. Gibaldi, M., Boyes, R. N. and Feldman, S. (1971). The influence of first pass effect on availability of drugs. J. Pharm. Sci. 60, 1338~1340.
24. Gramatté, T. and Richter, K. (1993). Paracetamol absorption from different sites in the human small intestine. Br. J. Clin. Pharmacol. 37, 608~611.
25. Hahn, T. W., Henneberg, S. W., Holm-Knudsen, R. J., Eriksen, K., Rasmussen, S.
- 77 -
N. and Rasmussen, M. (2000). Pharmacokinetics of rectal paracetamol after repeated dosing in children. Br. J. Anaesth. 85, 512~519.
26. Hogben, C. A. M., Tocco, D. J., Brodie, B. B. and Schanker, L. S. (1959). On the mechanism of intestinal absorption of drugs. J. Pharmacol. Exp. Ther. 125, 275~282.
27. Isac, M. D., García, M. A., Aguilera, J. F. and Molina Alcaide, E. A. (1994).
Comparative study of nutrient digestibility, kinetics of digestion and passage and rumen fermentation pattern in goats and sheep offered medium quality forages at the maintenance level of feeding. Arch. Tierernahr. 46, 37~50.
28. Jenkins, W. L., Davis, L. E. and Boulos, B. M. (1975). Transfer of drugs across the ruminal wall in goats. Am. J. Vet. Res. 36, 1771~1776.
29. John, V. A. (1979). The pharmacokinetics and metabolism of diclofenac sodium (Voltarol) in animals and man. Rheumatol. Rehabil. 2, 22~37.
30. Knoppert, N. W., Nijmeijer, S. M., van Duin, C. T., Korstanje, C., van Gogh, H. and van Miert, A. S. J. P. A. M. (1988). Some pharmacokinctic data of aditoprim and trimethoprim in healthy and tick-borne fever infected dwarf goats. J. Vet. Pharmacol.
Therap. 11, 135~144.
31. Kokue, E., Shimoda, M., Sakurada, K. and Wada, J. (1988). Pharmacokinetics of oral sulfa drugs and gastric emptying in the pig. J. Pharmacobiodyn. 11, 549~554.
32. Lin, C. E., Lin, W. C., Chen, Y. C. and Wang, S. W. (1997). Migration behavior and selectivity of sulfonamides in capillary electrophoresis. J. Chromatogr. A. 19, 37~47.
33. Lipka, E. and Amidon, G. L. (1999). Setting bioequivalence requirements for drug development based on preclinical data: Optimizing oral drug delivery systems. J.
Control. Release. 62, 41~49.
- 78 -
34. Lohmann, K. L., Roussel, A. J., Cohen, N. D., Boothe, D. M., Rakestraw, P. C. and Walker, M. A. (2000). Comparison of nuclear scintigraphy and acetaminophen absorption as a means of studying gastric emptying in horses. Am. J. Vet. Res. 61, 310~315.
35. Marriner, S. E. and Bogan, J. A. (1979). The influence of the rumen on the absorption of drugs: Studies using meclofenamic acid administered by various routes to sheep and cattle. J. Vet. Pharmacol. Therap. 2, 109~115.
36. Marshall, T. S., Constable, P. D., Crochik, S. and wittek, T. (2005). Determination of abomasal emptying rate in suckling calves by use of nuclear scintigraphy and acetaminophen absorption. Am. J. Vet. Res. 66, 364~374.
37. Mayersohn, M. (1990). Principles of drug absorption. In: Banker, G. S. and Rhodes, C. T. [eds] Modern Pharmaceutics, 2nd ed., pp 23~90. Marcel Dekker. New York.
38. McManus, E. C., Washko, F. V. and Tocco, D. J. (1966). Gastrointestinal absorption and secretion of thiabendazole in ruminants. Am. J. Vet. Res. 27, 849~855.
39. Menasse, R., Hedwall, P. R., Kraetz, J., Pericin, C., Riesterer, L., Sallmann, A., Ziel, R. and Jaques, R. (1978). Pharmacological properties of diclofenac sodium and its metabolites. Scand. J. Rheumatol. 22, 5~16.
40. Moffat, A. C., Jackson, J. V., Moss, M. S. and Widdop, B. (1986 a). Analytical and toxicological data: Monographs. In: Moffat, A. C., Jackson, J. V., Moss, M. S. and Widdop, B., [eds] Clarke's Isolation and Identification of Drugs in Pharmaceuticals, Body Fuids, and Post-mortem Material. 2nd ed., pp. 849~850.The Pharmaceutical Press, London.
41. Moffat, A. C., Jackson, J. V., Moss, M. S. and Widdop, B. (1986 b). Analytical and toxicological data: Monographs. In: Moffat, A. C., Jackson, J. V., Moss, M. S. and
- 79 -
Widdop, B., [eds] Clarke's Isolation and Identification of Drugs in Pharmaceuticals, Body Fuids, and Post-mortem Material. 2nd ed., pp. 983~991.The Pharmaceutical Press, London.
42. Morishita, T., Yamazaki, M., Yata, N. and Kamada, A. (1973). Studies on absorption of drugs. 8. Physicochemical factors affecting the absorption of sulfonamides from the rat small intestine. Chem. Pharm. Bull. 21, 2309~2322.
43. Nielsen, P., Romvary, A. and Rasmussen, F. (1978). Sulphadoxine and trimethoprim in goats and cows: Absorption fraction, half-lives and the degrading effect of the ruminal flora. J. Vet. Pharmacol. Therap. 1, 37~46.
44. Nimmo, J. (1973). The influence of metoclopramide on drug absorption. Postgrad.
Med. J. 49 (suppl.4), 25~29.
45. Nimmo, J., Heading, R. C., Tothill, P. and Prescott, L. F. (1973). Pharmacological modification of gastric emptying effects of probantheline and metoclopramide on paracetamol absorption. Br. Med. J. 1, 587~589.
46. Nurullah, Ş., Senem, Ş., Güleren, Ö. and Adel, D. (2010). Determination of pKa values of some sulfonamides by LC and LC-PDA methods in acetonitrile-water binary mixtures. J. Braz. Chem. Soc. 21, 1952~1960.
47. OECD, (1995). Organisation for Economic Cooperation and Development.
Guidelines for the testing of chemcials. Section 1: Physical-chemical properties.
Guideline 107, partition coefficient (n-octanol/water: shake flask method). Paris, France.
48. Oberle, R. L., Das, H., Wong, S. L., Chan, K. K. H. and Sawchuk, R. J. (1994).
Pharmacokinetics and metabolism of diclofenac sodium in Yucatan miniature pigs.
Pharm. Res. 11, 698~703.