The pharmacokinetics of diclofenac sodium following intravenous and oral administration

Willis, J. V.; Kendall, M. J.; Flinn, R. M.; Thornhill, D. P.; Welling, Peter G.

doi:10.1007/bf00568201

Cited by 242 publications

(148 citation statements)

References 10 publications

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“…Table III shows model parameters estimated for diclofenac absorption. Total bioavailability was estimated to be 61% which is in accordance with values reported in the literature (31). Empirical Bayes Estimates for the GI transit parameters were normally distributed around 0, with reasonable shrinkage (respectively, 19%, 11% and 24% for residence times in stomach (antrum+fundus), proximal small intestine, and distal small intestine).…”

Section: Application Of Gitt Model To Diclofenac Datasupporting

confidence: 84%

A mechanism-Based Approach for Absorption Modeling: The Gastro-Intestinal Transit Time (GITT) Model

Hénin

Bergstrand

Standing

et al. 2012

AAPS J

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Abstract. Absorption models used in the estimation of pharmacokinetic drug characteristics from plasma concentration data are generally empirical and simple, utilizing no prior information on gastro-intestinal (GI) transit patterns. Our aim was to develop and evaluate an estimation strategy based on a mechanismbased model for drug absorption, which takes into account the tablet movement through the GI transit. This work is an extension of a previous model utilizing tablet movement characteristics derived from magnetic marker monitoring (MMM) and pharmacokinetic data. The new approach, which replaces MMM data with a GI transit model, was evaluated in data sets where MMM data were available (felodipine) or not available (diclofenac). Pharmacokinetic profiles in both datasets were well described by the model according to goodness-of-fit plots. Visual predictive checks showed the model to give superior simulation properties compared with a standard empirical approach (first-order absorption rate+lag-time). This model represents a step towards an integrated mechanism-based NLME model, where the use of physiological knowledge and in vitro-in vivo correlation helps fully characterize PK and generate hypotheses for new formulations or specific populations.

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Section: Application Of Gitt Model To Diclofenac Datasupporting

confidence: 84%

A mechanism-Based Approach for Absorption Modeling: The Gastro-Intestinal Transit Time (GITT) Model

Hénin

Bergstrand

Standing

et al. 2012

AAPS J

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“…All these values were quoted from the literature as follows: ketoprofen (Jamali and Brocks, 1990;Obach et al, 2008); imipramine (Shibata et al, 2002;Obach et al, 2008); lorazepam (Shibata et al, 2002); levofloxacin (Chien et al, 1997;Obach et al, 2008); zidovudine (Moore et al, 1995;Obach et al, 2008); diclofenac (Willis et al, 1979;Obach et al, 2008); furosemide (McCrindle et al, 1996;Obach et al, 2008); raloxifene (Heringa, 2003); gemfibrozil (Todd and Ward, 1988;Soars et al, 2002); mycophenolic acid (Bullingham et al, 1998); indomethacin (Alván et al, 1975;Cubitt et al, 2009); and telmisartan (Stangier et al, 2000b;Obach et al, 2008). dmd.aspetjournals.org CL po,human was calculated as the quotient of the individual predicted CL and predicted F (eq.…”

Section: Observed and Predicted Values Of Human CLmentioning

confidence: 99%

Human Pharmacokinetic Prediction of UDP-Glucuronosyltransferase Substrates with an Animal Scale-Up Approach

Deguchi¹,

Watanabe²,

Kurihara³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The aim of the current study was to evaluate the accuracy of allometric scaling methods for drugs metabolized by UDP-glucuronosyltransferases (UGTs), such as ketoprofen, imipramine, lorazepam, levofloxacin, zidovudine, diclofenac, furosemide, raloxifene, gemfibrozil, mycophenolic acid, indomethacin, and telmisartan. Human plasma clearance (CL) predictions were conducted from preclinical in vivo data by using multiple-species allometry with the rule of exponents and single-species allometric scaling (SSS) of mice, rats, monkeys, or dogs. Distribution volume at a steady state (V ss ) was predicted by multiple-species allometry or SSS of V ss . Oral plasma clearance (CL po ) was calculated under the assumption that F a ؋ F g was equivalent across species. Each of the results was compared with the observed parameter calculated from the clinical data after intravenous or oral administration. Multiple-species allometry and SSS of mice, rats, and dogs resulted in a similar accuracy of CL and CL po predictions. Monkeys tended to provide the most accurate predictions of human CL and CL po . The ability to predict the half-life, which was determined from CL and V ss predictions, was more accurate in SSS of rats and monkeys. The in vivo fraction metabolized by glucuronidation (f m,UGT ) in bile duct-cannulated monkeys was relatively similar to that of humans compared with other animal species, which likely contributed to the highest accuracy of SSS prediction of monkeys. On the basis of the current results, monkeys would be more reliable than other animal species in predicting human pharmacokinetics and f m,UGT for drugs metabolized by UGTs.

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“…DCF undergoes extensive first-pass metabolism in humans, and approximately 50% of the dose is systemically available (Willis et al, 1979). The majority of DCF is converted into metabolites, of which 65% are eliminated in urine with the remainder excreted in bile (Riess et al, 1978;Novartis, 2011).…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

et al. 2015

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Diclofenac (DCF) is a nonsteroidal anti-inflammatory drug commonly prescribed to reduce pain in acute and chronic inflammatory diseases. One of the main DCF metabolites is a reactive diclofenac acyl glucuronide (DCF-AG) that covalently binds to biologic targets and may contribute to adverse drug reactions arising from DCF use. Cellular efflux of DCF-AG is partially mediated by multidrug resistanceassociated proteins (Mrp). The importance of Mrp2 during DCFinduced toxicity has been established, yet the role of Mrp3 remains largely unexplored. In the present work, Mrp3-null (KO) mice were used to study the toxicokinetics and toxicodynamics of DCF and its metabolites. DCF-AG plasma concentrations were 90% lower in KO mice than in wild-type (WT) mice, indicating that Mrp3 mediates DCF-AG basolateral efflux. In contrast, there were no differences in DCF-AG biliary excretion between WT and KO, suggesting that only DCF-AG basolateral efflux is compromised by Mrp3 deletion. Susceptibility to toxicity was also evaluated after a single high DCF dose. No signs of injury were detected in livers and kidneys; however, ulcers were found in the small intestines. Furthermore, the observed intestinal injuries were consistently more severe in KO compared with WT. DCF covalent adducts were observed in liver and small intestines; however, staining intensity did not correlate with the severity of injuries, implying that tissues respond differently to covalent modification. Overall, the data provide strong evidence that (1) in vivo Mrp3 plays an important role in DCF-AG disposition and (2) compromised Mrp3 function can enhance injury in the gastrointestinal tract after DCF treatment.

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The pharmacokinetics of diclofenac sodium following intravenous and oral administration

Cited by 242 publications

References 10 publications

A mechanism-Based Approach for Absorption Modeling: The Gastro-Intestinal Transit Time (GITT) Model

A mechanism-Based Approach for Absorption Modeling: The Gastro-Intestinal Transit Time (GITT) Model

Human Pharmacokinetic Prediction of UDP-Glucuronosyltransferase Substrates with an Animal Scale-Up Approach

Multidrug Resistance-Associated Protein 3 Plays an Important Role in Protection against Acute Toxicity of Diclofenac

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