A novel technique for assessment of biliary secretion and enterohepatic circulation in the unrestrained conscious rat

Tomlinson, P. W.; Jeffery, Douglas A.; Filer, C. W.

doi:10.3109/00498258109045324

Cited by 20 publications

(7 citation statements)

References 11 publications

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“…injection of either 0.9% NaCI (control), or a 50 mg/ml solution of p-aminophenol hydrochloride (PAP; Aldrich) in 0.9% NaC1 to give a dose of 100 mg/kg body weight either 15 minutes prior to surgery (experiment I), or following a 24 h post-operative recovery period (experiment II). The common bile ducts of 12 rats(6 per experiment) were cannulated according to the method of Tomlinson et al (1981). In all experiments rats were housed in well ventilated animal rooms with regular light cycles (12h: 0700-1900 hours).…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

Gartland

Eason²,

Bonner³

et al. 1990

Arch Toxicol

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The effects of a glutathione depletor, buthionine sulphoximine (BSO) and biliary cannulation on the nephrotoxicity of p-aminophenol (PAP) have been investigated in the F344 rat. Pretreatment with BSO completely protected against the nephrotoxicity of a 50 mg/kg dose of PAP, assessed by clinical chemistry, renal histopathology, and 1H-NMR urinalysis. Biliary cannulation partially protects against nephrotoxicity induced by 100 mg/kg PAP. These data suggest that the nephrotoxicity of PAP may be due in part to the formation of a proximate toxic metabolite in the liver which is excreted in the bile, subsequently reabsorbed and transported via the systemic circulation to the kidney where the toxic effects occur.

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Section: Animals and Treatmentsmentioning

confidence: 99%

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

Gartland

Eason²,

Bonner³

et al. 1990

Arch Toxicol

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“…Indeed, the relative amounts of each metabolite eliminated during the first day indicate that glucuronidation and hydroxylation are more susceptible to enantioselective effects than the hydrolysis pathway. For all of these pathways, S-Casodex had an apparently higher rate of metabolism than R-Casodex, presumably indicating that S-Casodex has a higher affinity for each of the respective metabolic enzymes; however, for many compounds, each enantiomer may be preferentially metabolized via different pathways, as observed with carvedilol (Fujimaki et al 1991) and cromakalin (Tomlinson et al 1992).…”

Section: Discussionmentioning

confidence: 84%

“…For bile collection, 12 rats were anaesthetized using halothane and their common bile ducts cannulated using standard surgical procedures (Tomlinson et al 1981). They had their drinking water supplemented with glucose (5%w/v), NaCl (0.9%) and KCI (O.OS%) from 24h prior to surgery until the end of the experiment; they were allowed 24 h for recovery from surgery before receiving single oral doses of Ror S-labelled Casodex at 10mg/kg.…”

Section: Animalsmentioning

confidence: 99%

Enantioselective metabolism and pharmacokinetics of Casodex in the male rat

et al. 1995

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1. Casodex, a non-steroidal antiandrogen, is a racemic mixture of R-Casodex, the pharmacologically active (-)-enantiomer, and S-Casodex, the inactive (+)-enantiomer. Single oral doses of pseudo-racemic 14C-Casodex (10 mg/kg), prepared from mixtures of either 14C-labelled R-Casodex and unlabelled S-Casodex, or 14C-S-Casodex and unlabelled R-Casodex, were administered to the intact and bile duct-cannulated male rat. 2. Neither enantiomer underwent stereochemical inversion, but the pharmacokinetics of Casodex showed marked enantioselectivity. 3. After dosing R-labelled Casodex, plasma concentrations of R-Casodex increased slowly to reach a peak of 3.50 +/- 0.05 micrograms/ml (mean +/- SEM) at 12 h and, thereafter, declined monoexponentially with an elimination half-life of 24 h. Plasma concentrations of S-Casodex rose rapidly to reach a much lower peak of 0.97 +/- 0.06 microgram/ml at 3 h and, thereafter, declined rapidly, although there were insufficient data to determine the half-life. R-Casodex had a much higher AUC0-24 (66 micrograms.h/ml) than S-Casodex (12 micrograms.h/ml). Plasma drug concentrations measured using an achiral assay were in very good agreement with the sum of the enantiomer concentrations throughout the profile. R-Casodex comprised 94% of the total plasma radioactivity at 12 h, decreasing to 75% at 120 h. 4. Plasma concentration data generated after administration of S-Casodex were similar to those observed after dosing R-labelled Casodex. S-Casodex comprised about 74% of the total plasma radioactivity at 6 h and only 41% at 24 h. 5. The urine of intact animals contained 36 +/- 2 and 48 +/- 3% of the dose respectively up to 48 and 120 h after dosing with R-labelled Casodex, and 33 +/- 4 and 34 +/- 4% respectively after dosing with S-labelled Casodex. The urine and bile of the cannulated rat contained 43 +/- 2 and 21 +/- 2% of the dose respectively up to 48 h after dosing with R-labelled Casodex and 37 (n = 2) and 50% respectively after dosing with S-labelled Casodex. 6. After dosing with R- or S-labelled Casodex, the urinary radioactivity consisted of the carboxylic acid metabolite formed by hydrolytic cleavage at the amide, whereas biliary radioactivity consisted of hydroxy-Casodex and Casodex, mainly conjugated with glucuronic acid. The clearance of R-Casodex by each of these pathways of metabolism was less than that of S-Casodex, with direct glucuronidation and hydroxylation showing greater enantioselectivity than hydrolysis.

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“…Bile-duct cannulation provides a way to examine the biliary excretion and potential enterohepatic circulation [26,27] and thus contributes useful information on the rate and extent of excretion of drug and/or metabolites via biliary pathways. Biliary excretion studies can be conducted by surgically ligating the common bile duct and inserting a cannula for bile collection [28] (see also Fig. 9.2).…”

Section: Bilementioning

confidence: 99%

Mass Balance Studies in Animals and Humans

Lin¹,

Heimbach²,

Gollen³

et al. 2012

Encyclopedia of Drug Metabolism and Interactions

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Before first‐in‐human (FIH) studies with a new drug candidate, preclinical studies need to be conducted to fulfill regulatory requirements or to facilitate regulatory approval. In the United States, investigational new drug (IND) applications with the Food and Drug Administration (FDA) may include IND enabling studies, such as (i) in vitro and in vivo pharmacology studies for intended use, (ii) toxicology studies supporting the starting dose and duration of an FIH study (such as single‐ or multiple‐dose studies in one rodent and nonrodent species with toxicokinetics, genotoxicity battery, safety pharmacology battery), (iii) single‐dose pharmacokinetics (PKs) in one rodent and nonrodent species, (iv) in vitro plasma protein binding in relevant species, and (v) in vitro cross species metabolism study in relevant species. While not mandatory for IND submissions, comprehensive preclinical absorption, distribution, metabolism, and excretion (ADME) studies, including biotransformation or metabolite profiling, conventional mass balance, or tissue distribution by quantitative whole‐body autoradiography (QWBA) studies can make a submission package more compelling for progression toward phase I clinical studies. Typically, preclinical ADME together with mass balance studies are recommended before conducting human ADME and mass balance studies, which are generally initiated after the successful synthesis of the radiolabeled drug. For preclinical ADME species, the selection of doses is often based on pre‐existing toxicity information and targeted therapeutic doses. For human ADME studies, which include the evaluation of mass balance, a relevant dose in the anticipated therapeutic range is typically chosen. Conventional mass balance studies only allow the calculation of mass recovery and PK parameters of the radiolabeled drug by quantification of the radioactivity present in excreta such as urine, feces, or bile. Nowadays, these mass balance studies are often conducted as part of more comprehensive ADME studies, where additional information is obtained, including (i) PK properties of the drug and its metabolite(s) in blood or plasma; (ii) absorption estimates via plasma/blood data, urinary data, or fecal data; (iii) elimination pathways and drug metabolism; (iv) total drug exposure and its metabolites in different organs and tissues at different time intervals. In this chapter, fundamental scientific considerations for the successful design, conduct, and interpretation of conventional, basic mass balance and more comprehensive ADME studies are reviewed and discussed.

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A novel technique for assessment of biliary secretion and enterohepatic circulation in the unrestrained conscious rat

Cited by 20 publications

References 11 publications

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

Enantioselective metabolism and pharmacokinetics of Casodex in the male rat

Mass Balance Studies in Animals and Humans

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