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Biomedical subjects

R F Witkamp

Publications and source records attributed to R F Witkamp.

At least 19 recordsLinked to original sources
PubMed1998

Congener specific PCB and polychlorinated camphene (toxaphene) levels in Svalbard ringed seals (Phoca hispida) in relation to sex, age, condition and cytochrome P450 enzyme activity.

Congener specific PCB and toxaphene (polychlorinated camphene, PCC) analyses were performed in seal blubber, collected in Svalbard, Norway. The concentration, body burden and metabolic index (PCB congener concentration in seal relative to their prey) were calculated. Multiple regression analyses were carried out to evaluate the influence of age, sex, blubber (as a percentage of total body weight) and cytochrome P450 activities on PCB and PCC levels. Levels of total PCBs found were five times higher than in ringed seals from the Canadian Arctic, corresponding with the relatively high contaminant levels in the European Arctic. The dominant PCB congeners (> 70% of the total PCBs measured) were 153, 138, 99, 180 and 101. The observed PCB and PCC accumulation patterns were very similar to patterns in seals from other studies, suggesting a large resemblance in contaminant metabolism. A decrease in the relative abundance of the lower chlorinated PCBs, was associated with higher concentrations of PCB 153. Since there was no indication for selective PCB excretion by lactating females, this suggests metabolism of these PCBs in ringed seals due to xenobiotic metabolising enzymes. The metabolic index confirmed the model of persistency of the different PCBs except for congener 128 and 138. These congeners, considered persistent in seals, could to some extent be metabolised in ringed seals. However, co-elution of PCB 138 with PCB 163 and of PCB 128 with TOX 50 possibly has resulted in an underestimation of the metabolic index for these congeners. Multiple regression analyses revealed a significant positive effect of age and a negative effect of the blubber content on the PCB concentrations. Since large fluctuations of body lipids occur between seasons in pinnipeds, PCB measurements should account for the total blubber content to avoid biased results. PCBs with vicinal H-atoms in the o, m or the m, p positions showed in addition a relation with cytochrome P450 enzyme activities. Surprisingly, no effect of sex on the PCB concentrations was observed, probably because female ringed seals, unlike other pinnipeds, continue feeding during lactation. This results in only small amounts of lipid and lipid-associated contaminants being mobilised from the blubber. Consequently, contaminant excretion with the milk will be low. Toxaphene concentrations found were low compared to levels found in the Canadian Arctic. Two congeners, TOX 26 and TOX 50 were predominant (15 and 18%, respectively of total toxaphene). There was no effect of sex, age, total blubber, or cytochrome P450 activities on the toxaphene levels. There was also no correlation between toxaphene and PCB levels, which may indicate differences in exposure and metabolism between these contaminants. Toxaphenes did not bioaccumulate to any substantial extent in ringed seals.

Adipose Tissue↗
PubMed1997

Differential inhibitory effects of phenytoin, diclofenac, phenylbutazone and a series of sulfonamides on hepatic cytochrome P4502C activity in vitro, and correlation with some molecular descriptors in the dwarf goat (Caprus hircus aegagrus).

1. The aim of the present study was to investigate the potency of various sulfonamides to inhibit tolbutamide hydroxylation (a CYP2C activity) in hepatic microsomal fractions and hepatocytes of the dwarf goat. Also a number of suggested substrates for human CYP2C9 was investigated. 2. From Dixon plots (microsomal fractions) it was observed that all compounds were competitive inhibitors of tolbutamide hydroxylation. Phenytoin (PT) showed the lowest Ki. Ki for the sulfonamides ranged between 205 and 4546 microM, sulfadoxine having the lowest Ki followed by sulfadimethoxine, sulfamoxole, sulfadimidine and sulfaphenazole. 3. In hepatocytes sulfaphenazole and diclofenac were the most potent inhibitors. 4. Out data indicate that PT, diclofenac (DF) and phenylbutazone (PBZ) are relative strong competitive inhibitors of tolbutamide hydroxylation and they are probably also substrates for the same enzyme. Differential inhibition of tolbutamide hydroxylation by sulfonamides was observed. 5. Correlation of structural parameters with the inhibition constant or the inhibition in hepatocytes showed that molecular volume, polarizability and molecular surface area are important parameters in determining the rate of inhibition of tolbutamide hydroxylation by sulfonamides in both microsomes and hepatocytes. In addition, log Poct are also involved in determining inhibition constants in microsomal fractions.

Animals↗
PubMed1996

Differential effect of pentoxifylline on lipopolysaccharide-induced downregulation of cytochrome P450.

It is now established that inflammatory stimuli such as lipopolysaccharides (LPS) and polyinosinic acid:polycytidylic (polyIC) suppress hepatic expression of cytochrome P450 (P450) genes in rat liver. Previous studies have suggested that LPS- or polyIC-induced downregulation of P450 was due to endogenously released inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1, interleukin-6, and interferons (IFNs). To improve our understanding of the role of inflammatory cytokines in mediating P450 depression, we investigated the possibility of preventing P450 downregulation with pentoxifylline. Pentoxifylline has been shown to inhibit LPS-induced TNF-alpha production by suppression of TNF-alpha gene expression. The present study shows that in uninduced male rats pentoxifylline selectively prevents the downregulation of microsomal P4501A2 and P4502B caused by LPS. No protective effect of pentoxifylline on the downregulation of P4502E1 and P4503A1/2 was observed. PolyIC-induced downregulation of P4501A2, P4502B, P4502E1, and P4503A1/2 was not affected by pentoxifylline. These results suggest that the LPS-induced downregulation of P4501A2 and P4502B is mediated to a large extent by TNF-alpha. Other cytokines might be involved in the suppression of P4502E1 and P4503A1/2. The fact that polyIC-induced downregulation is not protected by pentoxifylline is further evidence that this agent acts via a selective induction of IFNs.

Animals↗
PubMed1996

Suppression of cytochrome P450- and UDP glucuronosyl transferase-dependent enzyme activities by proinflammatory cytokines and possible role of nitric oxide in primary cultures of pig hepatocytes.

Proinflammatory cytokines play an important role in the depression of cytochrome P450 (CYP450)-dependent drug metabolism in mammals during inflammation and infection. Although much has been learned concerning the effects and mechanisms of cytokine-mediated suppression of CYP450, there is limited knowledge about how cytokines affect UDP glucuronosyl transferases (UDPGT). The aim of the present study was to investigate the effects and dose dependency of recombinant human proinflammatory cytokines on both CYP450- and UDPGT-dependent enzyme activities in primary cultures of pig hepatocytes. A possible role of nitric oxide in cytokine-induced suppression of enzyme activities was studied by incubating hepatocytes in the presence of N G-nitro-L-arginine (L-NAME), a competitive inhibitor of nitric oxide (NO) biosynthesis. Incubation of hepatocytes with interleukin-1alpha (IL-1alpha), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) decreased both oxidation and glucuronidation activities dose dependently, in which the effects on glucuronidation activities were even more pronounced. IL-6 differed from IL-1alpha and TNF-alpha by inhibiting CYP450 and UDPFT more effectively after 24 hr of incubation, whereas the inhibition by IL-1alpha and TNF-alpha was more pronounced after 12 hr. Only at a concentration of 500 U/ml did interferon-gamma (IFN-ganna) inhibit CYP450 and UDPGT. The inhibition of CYP450 enzyme activities by cytokines was probably not due to the production of NO, because L-NAME totally blocked NO production but had no effect on the cytokine-induced suppression of CYP450 enzyme activities. However, there might be a role for NO in the decrease of glucuronidation by cytokines, as L-NAME slightly though significantly prevented the inhibition of glucuronidation.

Acute-Phase Reaction↗
PubMed1996

Cytochrome P4502E in vivo and in vitro in the dwarf goat: effects of enzyme induction and the applicability of chlorzoxazone as marker substrate.

Cytochrome P4502E activities, inducibility and the applicability of chlorzoxazone as a marker substrate for this enzyme were investigated in female dwarf goats. Goats were treated with either isoniazid or beta-naphthoflavone. Treatment with isoniazid resulted in a 1.4 fold increase of the chlorzoxazone hydroxylation rate in hepatic microsomes. Aniline- and p-nitrophenol hydroxylation rates were increased by roughly the same extent (1.6 and 1.25 fold resp.) and increased levels of cytochrome P4502E apoproteins were found by Western blotting. Treatment with the cytochrome P4501A inducer beta-naphthoflavone resulted in a 2.5 fold induction of the in vitro chlorzoxazone hydroxylation rate, whereas the hydroxylation rates of aniline and p-nitrophenol were not induced. After treatment with isoniazid, chlorzoxazone plasma clearance was increased from 5.0 mL/min/kg to 11.0 mL/min/kg. Chlorzoxazone was almost completely excreted in the urine as conjugated hydroxy metabolites. These results do not support the hypothesis that cytochrome P4502E is of particular importance in goats, as has been suggested earlier. Furthermore, chlorzoxazone has limited value as a marker substrate for this enzyme, since cytochrome P4501A enzymes appear to play an important role in its biotransformation.

Aniline Compounds↗
PubMed1996

A lipopolysaccharide-induced acute phase response in the pig is associated with a decrease in hepatic cytochrome P450-mediated drug metabolism.

Drug disposition, including hepatic drug metabolism, is markedly affected by infection, inflammation and other conditions that invoke the acute phase response. In the present study, an Escherichia coli lipopolysaccharide (LPS)-induced acute phase response model was developed in pigs. This model was used to study the effects of the acute phase response on drug disposition and hepatic drug metabolism in vivo and in microsomal preparations. The results obtained were compared with those from Actinobacillus pleuropneumoniae-infected pigs. Intermittent intravenous administration of LPS induced a mild acute phase response as evidenced by increased rectal body temperatures, anorexia and increased cytokine (TNF-alpha and IL-6) serum levels within 1-2 h after the first LPS injection. The acute phase response is associated with a pronounced decrease of antipyrine plasma clearance (control 8.5 +/- 0.8 vs. LPS 2.2 +/- 0.7 mL/min.kg). Furthermore, total cytochrome P450 content and microsomal cytochrome P450-dependent activities were significantly decreased after 24 h. The decrease in cytochrome P450 activities was accompanied by losses of cytochrome P4501A and P4503A apoproteins. The microsomal glucuronidation rate of 1-naphthol was not affected in LPS-treated pigs. Comparing the LPS model with our previous findings in the Actinobacillus pleuropneumoniae model showed a remarkable similarity with regard to the effects on hepatic drug metabolism.

Animals↗
PubMed1996

Cytochrome P-450 complex formation in rat liver by the antibiotic tiamulin.

Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds. It has been suggested that this is caused by a selective inhibition of oxidative drug metabolism via the formation of a cytochrome P-450 metabolic intermediate complex. In the present study, rats were treated orally for 6 days with tiamulin at two different doses: 40 and 226 mg/kg of body weight. For comparison, another group received 300 mg of triacetyloleandomycin (TAO) per kg, which is equivalent to the 226-mg/kg tiamulin group. Subsequently, microsomal P-450 contents, P-450 enzyme activities, metabolic intermediate complex spectra, and P-450 apoprotein concentrations were assessed. In addition, effects on individual microsomal P-450 activities were studied in control microsomes at different tiamulin and substrate concentrations. In the rats treated with tiamulin, a dose-dependent complex formation as evidenced by its absorption spectrum and an increase in cytochrome P-4503A1/2 contents as assessed by Western blotting (immunoblotting) were found. The effects were comparable to those of TAO. Tiamulin induced microsomal P-450 content, testosterone 6 beta-hydroxylation rate, erythromycin N-demethylation rate, and the ethoxyresorufin O-deethylation activity. Other activities were not affected or decreased. When tiamulin was added to microsomes of control rats, the testosterone 6 beta-hydroxylation rate and the erythromycin N-demethylation were strongly inhibited. It is concluded that tiamulin is a potent and selective inducer-inhibitor of cytochrome P-450. Though not belonging to the macrolides, the compound produces an effect on P-450 similar to those of TAO and related compounds.

Animals↗
PubMed1996

Inhibition of tolbutamide 4-methylhydroxylation by a series of non-steroidal anti-inflammatory drugs in V79-NH cells expressing human cytochrome P4502C10.

1. To study the role of cytochrome P4502C10 in the metabolism of the non-steroidal antiinflammatory drugs (NSAIDs) diclofenac, phenylbutazone, fenoprofen, ibuprofen, flurbiprofen, ketoprofen and naproxen, a cell line was developed stably expressing CYP2C10 cDNA. A retroviral vector construct, containing a human CYP2C10 cDNA, was transfected in V79-NH Chinese hamster lung cells by calcium phosphate co-precipitation. Sublines stably expressing human cytochrome P450 cDNA were established by selection with the neomycin analogue G418. 2. Enzymatic activity of CYP2C10 was detected by 4-methylhydroxylation of tolbutamide. This activity was inhibited to background levels by preincubation with the CYP2C9/10 inhibitor sulphaphenazole. 3. Preincubations with the NSAIDs ketoprofen, phenylbutazone, flurbiprofen and diclofenac (all 250 microM) caused a decrease in 4-methylhydroxylation of tolbutamide (500 microM), significantly different from control values (p < 0.05). Inhibition of this activity was not seen in preincubations with the NSAIDs fenoprofen, ibuprofen and naproxen (250 microM). 4. The V79-NH CYP2C10 cell line we have developed has been shown to be a useful tool to predict drug-drug interactions.

Animals↗
PubMed1996

Gender differences in ethanol oxidation and cytochrome P4502E1 content and functions in hepatic microsomes from alcohol-preferring and non-preferring rats.

1. We have studied the hepatic microsomal metabolism of ethanol (MEOS), CYP2E1 expression and catalytic activity, and the response to phenobarbital (PB) induction or CCl4 challenge in rats of either sex genetically selected for their preference (P) or aversion (NP) for ethanol. 2. In P versus NP females, the amount of both total cytochrome P450 and P450 binding to metyrapone was lower, whereas the activities of MEOS, aniline 4-hydroxylase (4-AOH), and 4-nitrophenol hydroxylase (PNP-OH) as well as the level of immunodetectable CYP2E1 content were consistently higher. By contrast, no substantial differences were observed between P and NP males. 3. Despite an apparent down-regulation of CYP2E1 expression occurring in all rats as a result of PB induction, P females maintained higher 2E1 levels and showed enhanced MEOS, 4-AOH and PNP-OH activities with respect to NP females. No such changes were detected in the male counterparts. 4. No sex-related differences in CCl4-mediated inhibition of monooxygenase or MEOS activities were evident between P and NP animals. 5. These results indicate that, in females only, the behavioural trait of ethanol preference is apparently associated not only with higher constitutive levels of CYP2E1 and rate of microsomal metabolism of ethanol but also with altered susceptibility to PB induction.

Alcohol Drinking↗
PubMed1996

In vitro and in vivo oxidative biotransformation in the West-African dwarf goat (Caprus hircus aegagrus): substrate activities and effects of inducers.

1. Cytochrome P450 activities in vivo and in vitro and enzyme induction by phenobarbital, beta-naphthoflavone, isoniazid and triacetyloleandomycin were investigated in the female dwarf goat. In vivo kinetics of antipyrine, sulphadimidine and caffeine were studied separately and as a combination ("cocktail'). After establishing a lack of interaction between these compounds the effects of the inducing agents were investigated. In vitro, hepatic microsomal enzyme activities and apoprotein levels were determined. 2. In the beta-naphthoflavone treated goat, the microsomal ethoxy-resorufin-O-deethylation rate was markedly increased. beta-naphthoflavone also induced caffeine plasma clearance but did not affect microsomal caffeine 1- and 3-demethylation rates. After phenobarbital treatment, caffeine plasma clearance was also increased. In contrast with beta-naphthoflavone treatment, phenobarbital treatment resulted in an increase of microsomal caffeine 1- and 3-demethylation rates. 3. Goat liver microsomes were able to hydroxylate tolbutamide, predominantly a CYP2C9 activity in man, and debrisoquine, a CYP2D activity in different species. These activities were not affected by either beta-naphthoflavone or phenobarbital. Sulphaphenazole was found to be a more potent inhibitor of tolbutamide hydroxylation than sulphadimethoxine. Quinine was a more potent inhibitor of debrisoquine hydroxylation than was quinidine. 4. As expected, the microsomal aniline-4-hydroxylation rate (CYP2E) was increased after isoniazid treatment. 5. The microsomal testosterone 6 beta-hydroxylation rate (CYP3A) was increased after phenobarbital and triacetyloleandomycin treatment. Antipyrine plasma clearance was also increased after phenobarbital treatment. 6. As cytochrome P450 activities and inducibility in the dwarf goat show many resemblances to those in man, they may be of value as a model for human biotransformation research.

Animals↗
PubMed1995

Tiamulin inhibits human CYP3A4 activity in an NIH/3T3 cell line stably expressing CYP3A4 cDNA.

Tiamulin is an antibiotic frequently used in veterinary medicine. The drug has been shown to produce clinically important interactions with other compounds that are administered simultaneously. An NIH/3T3 cell line, stably expressing human cytochrome P450 (EC 1.14.14.1) cDNA (CYP3A4), was used to study the effect of tiamulin on CYP3A4 activity. The 6 beta-hydroxylation activity of testosterone, which is increased in CYP3A4-expressing cells compared to vector-transfected cells, showed reduced activity after incubation with 1 microM tiamulin and was completely reduced to background level after incubation with 2, 5 and 10 microM tiamulin. The CYP3A4-expressing cell line was used in combination with a shuttle vector containing the bacterial lacZ' gene to study the effect of tiamulin on CYP3A4-mediated mutagenicity of aflatoxin B1. The mutation frequency of aflatoxin B1 could be completely inhibited by tiamulin in CYP3A4-expressing cells, but no effect was observed on the mutation frequency of the direct mutagen ethylmethanesulphonate. Western blotting of homogenates of the CYP3A4-expressing cell line showed stabilization of CYP3A4 protein after incubation with tiamulin, supporting the hypothesis that the mechanism of inhibition is by binding of tiamulin to the cytochrome.

3T3 Cells↗
PubMed1995

Oral bioavailability and pharmacokinetics of baquiloprim in dwarf goats.

The pharmacokinetics of baquiloprim at a dose of 8 mg kg-1 bodyweight were determined after its intravenous and intra-ruminal administration to seven healthy female dwarf goats. After intravenous injection, the plasma elimination curve showed a rapid distribution phase (mean [SD] t1/2 alpha 0.89 [0.4] hours). The mean volume of distribution at steady-state (Vdss) was 14.1 (2.7) litres kg-1 bodyweight. The mean elimination half-life (t1/2 beta) was 14.0 (2.3) hours. After intra-ruminal administration its maximum concentration in plasma (Cmax) was 0.09 (0.01 microgram ml-1 and this maximum was not reached until approximately 35 hours after administration. The systemic oral bioavailability, calculated up to 48 hours after dosing, was 33.7 (7.1) per cent. Owing to a prolonged absorption phase, the data from only four of the goats fitted reasonably to a compartmental model.

Administration, Oral↗
PubMed1995

Oral bioavailability of sulphonamides in ruminants: a comparison between sulphamethoxazole, sulphatroxazole, and sulphamerazine, using the dwarf goat as animal model.

The various sulphonamides show marked differences in disposition characteristics after administration to ruminants. For use in combination with a diaminopyrimidine derivative such as trimethoprim or baquiloprim, it is essential that a sulphonamide has similar pharmacokinetic properties in order to obtain optimal synergy. In the present study the pharmacokinetics of sulphamethoxazole, sulphatroxazole, and sulphamerazine were investigated in dwarf goats (n = 6) after IV and intraruminal administration at a dose of 30 mg/kg bodyweight. In addition, the in vitro binding of sulphamerazine to ruminal contents was studied as a possible explanation for a reduced absorption rate. Sulphamethoxazole showed the most rapid absorption after intraruminal administration (mean tmax +/- SD : 0.8 +/- 0.2h). However, the drug was rapidly eliminated from the plasma (t1/2 beta : 2.4 +/- 1.5 h) and the bioavailability was only 12.4 +/- 4.7%, most likely due to an extensive 'first-pass' effect. The bioavailability of orally administered sulphamerazine and sulphatroxazole was much higher (67.6 +/- 13.5% and 70.2 +/- 32.3%, respectively). After intraruminal administration, sulphatroxazole showed the highest plasma peak concentration (26.1 +/- 6.3 mg/l) and the longest plasma half-life (4.7 +/- 1.8h) and mean residence time (13.9 +/- 4.5 h). Sulphamerazine showed considerable binding to rumen contents in vitro. Based on its pharmacokinetic properties sulphatroxazole appears to be a suitable candidate to be used in combination with the more recently developed diaminopyrimidines such as baquiloprim.

Administration, Oral↗
PubMed1995

Selective effects of a bacterial infection (Actinobacillus pleuropneumoniae) on the hepatic clearances of caffeine, antipyrine, paracetamol, and indocyanine green in the pig.

1. In order to investigate the effect of a bacterial acute phase response model on drug disposition in vivo, plasma clearances of antipyrine, caffeine, paracetamol and indocyanine green were investigated in the healthy and Actinobacillus pleuropneumoniae-infected pig. 2. Indocyanine green plasma and endogenous creatinine clearance were not changed during the infection, which indicates that hepatic blood flow and renal function were not significantly affected. 3. In the A. pleuropneumoniae-infected pig, plasma clearances of antipyrine and caffeine, both marker substrates for hepatic oxidative biotransformation, were decreased by 72 and 68% respectively. The clearance of paracetamol, a drug mainly glucuronidated in the pig, was reduced by 39%. 4. It is concluded that the most important change in drug elimination during an acute phase response induced by A. pleuropneumoniae is a suppression of oxidative hepatic biotransformation.

Acetaminophen↗
PubMed1995

The antibiotic tiamulin is a potent inducer and inhibitor of cytochrome P4503A via the formation of a stable metabolic intermediate complex. Studies in primary hepatocyte cultures and liver microsomes of the pig.

Tiamulin is a semisynthetic antibiotic frequently used in agricultural animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds that are simultaneously administered. To explain this, it has been suggested that tiamulin selectively inhibits oxidative drug metabolism via the formation of a cytochrome P450 metabolic intermediate complex. The aim of the present study was to provide further support for this hypothesis. When hepatic microsomes and cultured primary pig hepatocytes were incubated with tiamulin, a maximum in the absorbance spectrum at 455 nm was observed, which disappeared after adding KFe(CN)6. When hepatocytes were incubated with tiamulin for 72 hr, cytochrome P450 content and cytochrome P4503A apoprotein levels were increased. Tiamulin strongly inhibited and concentration dependently inhibited the hydroxylation rate of testosterone at the 6 beta-position in both microsomes and hepatocytes, and the microsomal N-demethylation rate of ethylmorphine. Other testosterone hydroxylations were inhibited to a lesser extent or not affected. The relative inhibition of the hydroxylation of testosterone at the 6 beta-position was more pronounced in microsomes from rifampicin- and triacetyloleandomycin-treated pigs. The results indicate that cytochrome P450 complex formation can at least partly explain the interactions observed with tiamulin. Tiamulin seems to be a strong, probably selective, inhibitor of the cytochrome P4503A subfamily and an interesting tool for further research.

Animals↗
PubMed1995

Infection (Actinobacillus pleuropneumoniae)-mediated suppression of oxidative hepatic drug metabolism and cytochrome P4503A mRNA levels in pigs.

The effect of Actinobacillus pleuropneumoniae infection, a well-characterized pig infection model, on both phase I (oxidative) and phase II (conjugative) microsomal enzyme activities was investigated in castrated male conventional pigs. A. pleuropneumoniae infection resulted after 24 hr in a significant suppression of 33% or more of all oxidative enzyme activities determined. After 40 hr, the activities were still suppressed, but did not differ from the results after 24 hr. On the contrary, all glucuronosyltransferase activities measured were not affected by A. pleuropneumoniae infection after both 24 and 40 hr. To elucidate further the mechanism of the suppression of oxidative enzyme activities, analysis of mRNA were conducted by dot-blot analysis using a human cytochrome P4503A4 cDNA probe. The results indicated that A. pleuropneumoniae infection suppressed oxidative enzyme activities. The reduction in cytochrome P4503A activity, specific for 6 beta-hydroxylation of testosterone is at a pretranslational level as measured by a decrease in the amount of mRNA.

Actinobacillus Infections↗
PubMed1994

Oral bioavailability of sulphamethoxydiazine, sulphathiazole and sulphamoxole in dwarf goats.

To get a better insight into the oral bioavailability of sulphonamides in ruminants, sulphamethoxydiazine (pKa 7.0), sulphathiazole (pKa 7.2), and sulphamoxole (pKa 7.4) were administered to dwarf goats (n = 5). The drugs were given at 2-week intervals by the intravenous or intraruminal route at a dose of 100 mg per kg body weight. After IV injection, the mean half-life (t1/2 beta in h +/- SEM) was 0.80 +/- 0.10 h, 2.35 +/- 0.38 h, and 3.36 +/- 1.25 h, for sulphathiazole, sulphamoxole, and sulphamethoxydiazine, respectively and the mean distribution volume (Vd beta) was 0.23 +/- 0.05 l/kg, 0.23 +/- 0.04 l/kg, and 0.33 +/- 0.02 l/kg. After intraruminal administration, the mean bioavailability varied from 86.0 +/- 11.8% for sulphamethoxydiazine to 46.6 +/- 4.3% for sulphamoxole, and 52.6 +/- 7.2% for sulphathiazole. The elimination half-life was significantly prolonged, probably due to a low rate of drug absorption from the gastrointestinal tract. In contrast to chloramphenicol, the sulphonamides studied were stable when incubated in rumen fluid at 39 degrees C.

Administration, Oral↗