Kinetics of biliary elimination of pentacaine in rats

Bezek, S; Ščasnár, V.; Kukan, M; Trnovec, T.

doi:10.1002/bdd.2510110505

Cited by 4 publications

(1 citation statement)

References 6 publications

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“…Four rats with surgically implanted bile cannulae, as described by Bezek et al (1990b), were dosed intraduodenally with 15 pCi [3H]GAZT (1 mg/rat) in 1 mL control bile diluted with 0.9% NaCI. Bile samples were collected in scintillation vials.…”

Section: Kinetics Of ['Higazt In-vivomentioning

confidence: 99%

Hepatobiliary Disposition of 3′-Azido-3′-deoxythymidine (AZT) in the Rat: Effect of Phenobarbitone Induction

Bezek

Kukan

Bohov

1994

Journal of Pharmacy and Pharmacology

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Isolated liver with a recirculating perfusate was used to study 3'-azido-3'-deoxythymidine (AZT) disposition in phenobarbitone-pretreated rats at 68 microM AZT concentration in the reservoir. Clearance of AZT in the livers obtained from control animals was 0.42 +/- 0.01 (mean +/- s.d.) mL min-1/10 g liver. Over the study period of 105 min, 12.7 +/- 2.6% of the dose was excreted in bile and of this 95% was recovered as 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranuronosylthymidine (GAZT). The amount of GAZT found in the perfusate after 105 min of liver perfusion was < 1% of the AZT dose introduced into the reservoir. Phenobarbitone pretreatment of rats resulted in a 5.5-fold increase of AZT clearance. In addition, the area under the perfusate concentration-time curve (AUC0-105 min) for 3'-amino-3'-deoxythymidine (AMT) and for a catabolite of unknown structure was increased 3- and 10-fold, respectively, and the amount of AZT dose excreted in the bile was nearly doubled. Thus phenobarbitone was capable of stimulating both detoxification of AZT to GAZT and bioactivation of AZT to AMT, a catabolite known to be highly toxic to human bone marrow cells. This induction was the result of enhancement of AZT catabolism rather than its transport into the cells, since on incubation of AZT (0-250 microM) with rat isolated hepatocytes, a linear relationship between concentration and amount taken up by the cells was shown. In addition, the rate of AZT uptake was not influenced by KCN, dinitrophenol, or temperature, which is consistent with a simple diffusion of AZT through the hepatocellular membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Kinetics Of ['Higazt In-vivomentioning

confidence: 99%

Hepatobiliary Disposition of 3′-Azido-3′-deoxythymidine (AZT) in the Rat: Effect of Phenobarbitone Induction

Bezek

Kukan

Bohov

1994

Journal of Pharmacy and Pharmacology

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Effects of inducers and inhibitors of mixed‐function oxidases on the biliary excretion of pentacaine metabolites

Kukan

Bezek

Ščasnár

et al. 1990

Biopharm & Drug Disp

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The biliary excretion of 3H-pentacaine and its metabolites was studied in rats pretreated with an inducer or inhibitor of mixed-function oxidases. Over one-fourth (25.8 per cent) of a 2 mg kg-1 intraportal dose of 3H-pentacaine was excreted in bile in urethaneanaesthetized control rats within 3 h. The radioactivity appeared in the form of the parent drug, basic metabolites, and metabolite conjugates, 3.1, 86.5, and 10.4 per cent of the total radioactivity excreted, respectively. Pretreatment of rats with phenobarbital enhanced only slightly the biliary excretion of basic metabolites, and pretreatment with 3-methylcholanthrene had no effect. Phenobarbital also increased the initial rate of excretion of conjugates, but this effect was not sustained. 3-Methylcholanthrene had a tendency to impair excretion of conjugates by bile. Pretreatment of rats with SKF 525-A decreased the biliary excretion of both basic metabolites and conjugates while cimetidine did not alter significantly the biliary excretion of pentacaine metabolites. These results suggest that the canalicular transport of metabolites may be the most important factor in controlling pentacaine metabolite excretion in bile.

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Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine

Sparreboom

Asperen

Mayer

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

790

488

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In mice, the mdr1a and mdr1b genes encode drug-transporting proteins that can cause multidrug resistance in tumor cells by lowering intracellular drug levels. These P-glycoproteins are also found in various normal tissues such as the intestine. Because mdr1b P-glycoprotein is not detectable in the intestine, mice with a homozygously disrupted mdr1a gene [mdr1a(؊͞؊) mice] do not contain functional P-glycoprotein in this organ. We have used these mdr1a(؊͞؊) mice to study the effect of gut P-glycoprotein on the pharmacokinetics of paclitaxel. The area under the plasma concentration-time curves was 2-and 6-fold higher in mdr1a(؊͞؊) mice than in wild-type (wt) mice after i.v. and oral drug administration, respectively. Consequently, the oral bioavailability in mice receiving 10 mg paclitaxel per kg body weight increased from only 11% in wt mice to 35% in mdr1a(؊͞؊) mice. The cumulative fecal excretion (0-96 hr) was markedly reduced from 40% (after i.v. administration) and 87% (after oral administration) of the administered dose in wt mice to below 3% in mdr1a(؊͞؊) mice. Biliary excretion was not significantly different in wt and mdr1a(؊͞؊) mice. Interestingly, after i.v. drug administration of paclitaxel (10 mg͞kg) to mice with a cannulated gall bladder, 11% of the dose was recovered within 90 min in the intestinal contents of wt mice vs. <3% in mdr1a(؊͞؊) mice. We conclude that Pglycoprotein limits the oral uptake of paclitaxel and mediates direct excretion of the drug from the systemic circulation into the intestinal lumen.

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Kinetics of biliary elimination of pentacaine in rats

Cited by 4 publications

References 6 publications

Hepatobiliary Disposition of 3′-Azido-3′-deoxythymidine (AZT) in the Rat: Effect of Phenobarbitone Induction

Hepatobiliary Disposition of 3′-Azido-3′-deoxythymidine (AZT) in the Rat: Effect of Phenobarbitone Induction

Effects of inducers and inhibitors of mixed‐function oxidases on the biliary excretion of pentacaine metabolites

Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine

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