Comparative disposition of sulindac and metabolites in five species

Duggan, D E; Hooke, K F; Noll, R.M.; Hücker, H.; Arman, C. G. Van

doi:10.1016/0006-2952(78)90137-5

Cited by 70 publications

(27 citation statements)

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“…Sulindac is metabolized extensively by the liver in rats and humans, and plasma concentrations of sulindac metabolites are sustained because of extensive enterohepatic recycling (Dujovne et al, 1983). After intravenous administration of sulindac (10 mg/kg) in rats, the plasma area under the concentration-time curve (AUC) for S-sulfone was ϳ2.5-fold higher than that of sulindac, whereas the AUC for S-sulfide was only ϳ40% of that for sulindac (Duggan et al, 1978); Cl biliary of sulindac and S-sulfone were comparable, whereas S-sulfide Cl biliary was only 40% of that for sulindac. In humans, after oral administration of sulindac, peak plasma total concentrations (C max ) for sulindac, S-sulfone, and Ssulfide were 10 to 34, 4 to 19, and 3 to 33 M, respectively (Davies and Morris, 1993); the apparent Cl biliary of sulindac and S-sulfone, measured by an occludable T-tube that was placed in the common bile duct of patients after elective gallbladder surgery, was ϳ25-and ϳ18-fold greater, respectively, than that of S-sulfide .…”

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confidence: 99%

“…In humans, after oral administration of sulindac, peak plasma total concentrations (C max ) for sulindac, S-sulfone, and Ssulfide were 10 to 34, 4 to 19, and 3 to 33 M, respectively (Davies and Morris, 1993); the apparent Cl biliary of sulindac and S-sulfone, measured by an occludable T-tube that was placed in the common bile duct of patients after elective gallbladder surgery, was ϳ25-and ϳ18-fold greater, respectively, than that of S-sulfide . Several groups have reported a proportional relationship between S-sulfide concentrations and the incidence of hepatotoxicity, emphasizing the potential for metabolites, in addition to the parent drug, to cause hepatotoxicity (Duggan et al, 1978;Laffi et al, 1986).…”

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Sulindac and Its Metabolites Inhibit Multiple Transport Proteins in Rat and Human Hepatocytes

Lee¹,

Paine²,

Brouwer³

2010

J Pharmacol Exp Ther

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Sulindac is a commonly used nonsteroidal anti-inflammatory drug. This study tested the hypothesis that sulindac-mediated drug-drug interactions and/or hepatotoxicity may be caused, in part, by inhibition of proteins responsible for the hepatic transport of drugs and/or bile acids by sulindac and/or sulindac metabolites [sulindac sulfone (S-sulfone) and sulindac sulfide (S-sulfide)]. The uptake and excretion of model substrates, [3 H]estradiol 17-␤-glucuronide (E217G), and nitrofurantoin (NF), were investigated in rat and human suspended and sandwich-cultured hepatocytes (SCH). In suspended rat hepatocytes, S-sulfone and S-sulfide inhibited Na ϩ -dependent TC initial uptake (IC 50 of 24.9 Ϯ 6.4 and 12.5 Ϯ 1.8 M, respectively) and Na ϩ -independent E217G initial uptake (IC 50 of 12.1 Ϯ 1.6 and 6.3 Ϯ 0.3 M, respectively). In rat SCH, sulindac metabolites (100 M) decreased the in vitro biliary clearance (Cl biliary ) of TC, E217G, and NF by 38 to 83%, 81 to 97%, and 33 to 57%, respectively; S-sulfone and S-sulfide also decreased the TC and NF biliary excretion index by 39 to 55%. In suspended human hepatocytes, S-sulfone and S-sulfide inhibited Na ϩ -dependent TC initial uptake (IC 50 of 42.2 and 3.1 M, respectively); S-sulfide also inhibited the TC Cl biliary in human SCH. Sulindac/metabolites markedly inhibited hepatic uptake and biliary excretion of E217G by 51 to 100% in human SCH. In conclusion, sulindac and metabolites are potent inhibitors of the uptake and biliary clearance of bile acids in rat and human hepatocytes and also inhibit substrates of rat breast cancer resistance protein, rat and human organic anion-transporting polypeptides, and human multidrug resistance-associated protein 2. Inhibition of multiple hepatic transport proteins by sulindac/metabolites may play an important role in clinically significant sulindac-mediated drug-drug interactions and/or liver injury.

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Sulindac and Its Metabolites Inhibit Multiple Transport Proteins in Rat and Human Hepatocytes

Lee¹,

Paine²,

Brouwer³

2010

J Pharmacol Exp Ther

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“…It is also metabolized irreversibly to an inactive sulfone (18,19). In vitro anti -inflammatory test systems considered relevant to in vivo efficacy and correlations between drug concentration and biological effect ex vivo suggest that sulindac is a prodrug.…”

Section: Reversible and Irreversible Conversionmentioning

confidence: 99%

Prodrugs for the improvement of drug absorption via different routes of administration

Balant

Doelker

Buri

1990

Eur. J. Drug Metab. Pharmacokinet.

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The authors critically review recent knowledge on the use of prodrugs to improve drug absorption. Main emphasis is placed on the parenteral, oral, transdermal and ocular routes. Mechanisms for drug absorption enhancement and bioavailability assessment are discussed. Some other applications of prodrugs are also examined. Finally, some comments are made regarding the present situation and future trends in prodrug design and their implications in biopharmaceutics and pharmacokinetics.

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“…As a sulfoxide compound, ruc-ML-1035 sulfoxide may also undergo substantial metabolic interconversion with its sulfide metabolite, as those have been reported for sulfinpyraand sulindac. 20, 21 Therefore, the enantiomeric outcome after a prochiral sulfide dose is also of importance.…”

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Disposition kinetics of ML‐1035 sulfoxide enantiomers and the prochiral sulfide in rats

Kuo¹,

Poole²,

Mandagere³

et al. 1993

Chirality

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ML-1035, 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2- (diethyl-amino)ethyl]benzamide, is a sulfoxide compound and a racemic gastroprokinetic agent with a chiral center at the sulfur atom. We have investigated the disposition kinetics of (R)-ML-1035 sulfoxide (R) and (S)-ML-1035 sulfoxide (S) after the single enantiomers and the racemic mixture were administered to rats in separate experiments. There was no noticeable chiral inversion after either enantiomer dose. Both enantiomers were rapidly absorbed. After dosing with enantiomers or with the racemate, the resulting plasma concentration-time curve of R was closely parallel to that of S in both intravenous and oral experiments, suggesting that the two enantiomers have approximately the same disposition kinetics. After intravenous enantiomer doses, only S underwent conversion to sulfide, suggesting that sulfidation in the liver is enantioselective. However, the enantioselective sulfidation after intravenous dosing did not introduce a difference in the global plasma disposition profiles between R and S, since the reduction reaction is a minor metabolic process. Other metabolic reactions such as sulfonation and mono-N-desethylations were not enantioselective. After oral administration, conversion to sulfide was observed for both enationers, implicating the existence of a nonhepatic pathway in sulfidation. Administration of a prochiral sulfide dose was associated with an enantioselective sulfoxidation, in which the R/S concentration ratios increased as a function of time. In addition, enatiomeric interaction causing changes in pharmacokinetic parameters was observed after the oral racemate dose, while the interaction is negligible after an intravenous racemate dose, indicating a route dependency in enantiomeric interaction.

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Comparative disposition of sulindac and metabolites in five species

Cited by 70 publications

References 8 publications

Sulindac and Its Metabolites Inhibit Multiple Transport Proteins in Rat and Human Hepatocytes

Sulindac and Its Metabolites Inhibit Multiple Transport Proteins in Rat and Human Hepatocytes

Prodrugs for the improvement of drug absorption via different routes of administration

Disposition kinetics of ML‐1035 sulfoxide enantiomers and the prochiral sulfide in rats

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