Pharmacokinetics of a sulphamethoxazole/trimethoprim formulation in pigs after intravenous administration

Nouws, J. F. M.; Vree, T. B.; Degen, Michael; Mevius, Dik

doi:10.1080/01652176.1991.9694300

Cited by 18 publications

(11 citation statements)

References 18 publications

(28 reference statements)

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“…The plasma concentration of TMP was maintained at 10.5 l m in the rat study (Takubo et al 2000a). Literature data indicate that the mean ratio of TMP concentration in kidney and plasma (C kidney }C plasma ) was about 10 in the elimination phase after rats received intravenous dose of TMP, and that the unbound fraction of TMP, as determined from the extent of its plasma protein binding, is 0.65 (Tu et al 1989;Nouws et al 1991;Gustafsson et al 1999). Based on these values, the ratio of the CLr was predicted to be 0.288, similar to the ratio observed in the rat study in vivo.…”

Section: Discussionmentioning

confidence: 95%

Uptake of lamivudine by rat renal brush border membrane vesicles

Takubo

Kato

Kinami

et al. 2002

Journal of Pharmacy and Pharmacology

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Uptake of lamivudine, a nucleoside analogue antiviral agent, by brush border membrane vesicles (BBMV) prepared from rat renal cortex was investigated. Initial uptake of lamivudine by BBMV was stimulated in the presence of an outward pH gradient. Determination of the kinetic parameters of the initial uptake yielded apparent Km and Vmax values of 2.28 mm and 1.56 nmol (mg protein)(-1) (20 s)(-1), respectively. The pH-driven uptake of lamivudine was inhibited by organic cations such as trimethoprim and cimetidine. The inhibitory effect of trimethoprim on lamivudine uptake was competitive, with an apparent Ki of 27.6 microM. The uptake of lamivudine was also inhibited by nitrobenzylthioinosine, a representative inhibitor of nucleoside transport, and by other nucleoside analogues, such as azidothymidine and dideoxycytidine, that are excreted by renal tubular secretion. These findings suggest that efflux of lamivudine at the brush border membrane of renal tubular epithelium is mediated by an H+/lamivudine antiport system, which may correspond to the H+/organic cation antiport system, and that this system is also involved in the renal secretion of other nucleoside analogues.

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Section: Discussionmentioning

confidence: 95%

Uptake of lamivudine by rat renal brush border membrane vesicles

Takubo

Kato

Kinami

et al. 2002

Journal of Pharmacy and Pharmacology

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“…In pigs, the main metabolic pathway for most sulfonamides is supposed to be N-acetylation (Vree et al, 1985a;Kinabo & Nielsen, 1986;Rehm et al, 1986;Nouws et al, 1989Nouws et al, , 1991Shimoda et al, 1990)). The rate and extent of the in vivo acetylation of sulfonamides is dependent on the structure of the sulfonamide.…”

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confidence: 99%

“…Furthermore, it was shown that after administration of N4-acetyl sulfonamides to humans and food-producing animals the compounds were partly deacetylated to the parent sulfonamide (Vree et al, 1985b;Nouws et al, 1989;Shimoda et al, 1990). The main metabolic pathway for TMP in pigs is Odemethylation with subsequent conjugation Gyrd-Hansen et al, 1984;Nouws et al, 1991). Two hydroxy metabolites are formed, 3'-and 4'-demethyl trimethoprim (also referred to as M4 and M1, respectively), which are glucuronidated and sulfated.…”

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confidence: 99%

The biotransformation of sulfadimethoxine, sulfadimidine, sulfamethoxazole, trimethoprim and aditoprim by primary cultures of pig hepatocytes

Mengelers¹,

Kleter²,

Hoogenboom³

et al. 1997

Vet Pharm & Therapeutics

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The in vitro biotransformation of three sulfonamides, trimethoprim and aditoprim, was studied using primary cultures of pig hepatocytes. Incubation of monolayer cultures with sulfadimethoxine (SDM), sulfamethoxazole (SMX) and 14C-sulfadimidine (SDD) resulted in the formation of the corresponding N4-acetylsulfonamide to different extents, depending upon the molecular structure of the drug. Addition of the acetylsulfonamides to the cells showed that these compounds were deacetylated, each to a different extent. A relatively low degree of acetylation (in the case of SDD) was paralleled by extensive deacetylation (i.e. AcSDD), whereas extensive acetylation (i.e. SMX) was in concert with minor deacetylation (i.e. AcSMX). The addition of bovine serum albumin to the medium resulted in a decrease in conversion of sulfonamides as well as acetylsulfonamides. The main metabolic pathway of 14C-trimethoprim (TMP) was O-demethylation with subsequent conjugation. Two hydroxy (demethyl) metabolites were formed, namely 3'- and 4'-demethyl trimethoprim, which were both glucuronidated while 3'-demethyl trimethoprim was also conjugated with sulphate. The capacity to form conjugates with either glucuronic acid or sulphate was at least as high as the capacity for O-demethylation since more than 90% of the metabolites were excreted as conjugates in the urine of pigs. Addition of 14C-aditoprim (ADP) to the hepatocytes led to the N-demethylation of ADP to mono-methyl-ADP and didesmethyl-ADP. During the incubation another three unknown ADP metabolites were formed. In contrast to TMP, no hydroxy metabolites or conjugated metabolites of aditoprim were formed. These in vitro results were in agreement with the in vivo biotransformation pattern of the studied sulfonamides and trimethoprim in pigs.

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“…The latter process probably contributes to ion trapping in the rumen, which may occur in the case of a weak organic base (Baggot, 1980) such as trimethoprim (Knoppert et al, 1988). Page et al (1991) have reported that there are similarities between horses and elephants in the metabolism of trimethoprim. According to Friis et al (1984) the metabolism of trimethoprim is the main factor in its elimination.…”

Section: Discussionmentioning

confidence: 99%

Interspecies comparisons of plasma half‐life of trimethoprim in relation to body mass

Pashov

Lashev

Matev

et al. 1997

Vet Pharm & Therapeutics

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The relationship between body mass and plasma half-life of trimethoprim was studied in 10 different species of animals and man using published data. Log half-life was positively and significantly correlated to log body mass based on individual measurements in herbivorous animals (n = 23, P < 0.01), in herbivorous animals+pigs (n = 29, P < 0.01), in ungulates (n = 27, P < 0.01), in ruminants (n = 16, P < 0.01) and in non-herbivorous mammals, except pigs (n = 6, P < 0.05). The correlation was described by the allometric equations: t 1/2 beta = 27 W0.26 in herbivorous animals and t 1/2 beta = 125 W0.32 in non-herbivorous animals except pigs.

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Pharmacokinetics of a sulphamethoxazole/trimethoprim formulation in pigs after intravenous administration

Cited by 18 publications

References 18 publications

Uptake of lamivudine by rat renal brush border membrane vesicles

Uptake of lamivudine by rat renal brush border membrane vesicles

The biotransformation of sulfadimethoxine, sulfadimidine, sulfamethoxazole, trimethoprim and aditoprim by primary cultures of pig hepatocytes

Interspecies comparisons of plasma half‐life of trimethoprim in relation to body mass

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