Age-and Dose-dependent Naproxen Disposition in Fischer 344 Rats

Satterwhite, J H; Boudinot, F. Douglas

doi:10.1093/geronj/46.6.b222

Cited by 8 publications

(5 citation statements)

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“…In patients, naproxen f u can vary up to eightfold in therapy, which can alter PD and consequently influence the occurrence and severity of side effects. Our findings for the f u of naproxen in rats and humans are comparable to published data (Satterwhite & Boudinot, 1991; Borga & Borga, 1997) and suggest that protein binding in rats is lower than in humans. In patients, naproxen f u can vary up to eightfold in therapy, which can alter PD and consequently influence the occurrence and severity side effects.…”

Section: Discussionsupporting

confidence: 91%

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Correlation between in vitro and in vivo concentration–effect relationships of naproxen in rats and healthy volunteers

Huntjens¹,

Spalding²,

Danhof³

et al. 2006

British J Pharmacology

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1 Understanding the mechanisms underlying the analgesic effect of new cyclooxygenase inhibitors is essential to identify dosing requirements in early stages of drug development. Accurate extrapolation to humans of in vitro and in vivo findings in preclinical species is needed to optimise dosing regimen in inflammatory conditions. 2 The current investigation characterises the inhibition of prostaglandin E2 (PGE 2 ) and thromboxane B2 (TXB 2 ) by naproxen in vitro and in vivo in rat and human blood. The inhibition of PGE 2 in the absence or presence of increasing concentrations of naproxen (10 À8 -10 À1 M) was measured by ex vivo whole blood stimulation with LPS, whereas inhibition of TXB 2 was measured in serum following blood clotting. In further experiments, inhibition of PGE 2 and TXB 2 levels was also assessed ex vivo in animals treated with naproxen (2.5, 10, 25 mg kg À1 ). Subsequently, pharmacokinetic (PK)/pharmacodynamics (PD) modelling of in vitro and in vivo data was performed using nonlinear mixed effects in NONMEM (V). 3 Inhibition of PGE 2 and TXB 2 was characterised by a sigmoid E max model. The exposure-response relationships in vitro and in vivo were of the same order of magnitude in both species. IC 80 estimates obtained in vitro were similar for PGE 2 inhibition (130.8711 and 131.9719 10 À6 M, mean7s.d. for humans and rats, respectively), but slightly different for TXB 2 inhibition (103.9715 and 151.4740 10 À6 M, mean7s.d. for humans and rats, respectively, Po 0.05). These differences, however, may not be biologically relevant. 4 The results confirm the value of exposure-effect relationships determined in vitro as a means to predict the pharmacological activity in vivo. This analysis also highlights the need to parameterise concentration-effect relationships in early drug development, as indicated by the estimates of IC 80 for PGE 2 and TXB 2 inhibition.

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Section: Discussionsupporting

confidence: 91%

“…Our validation procedures demonstrated the precision and stability of the two‐compartment model for the PK of naproxen. The population parameter estimates for CL (0.694 ml min −1 kg −1 ) and V ss (249 ml kg −1 ) were in agreement with those published previously by Satterwhite & Boudinot (1991) and Josa et al . (2001).…”

Section: Discussionsupporting

confidence: 91%

Correlation between in vitro and in vivo concentration–effect relationships of naproxen in rats and healthy volunteers

Huntjens¹,

Spalding²,

Danhof³

et al. 2006

British J Pharmacology

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“…Other authors [21] found no changes in AGP levels depending on the age or a marked decrease in AGP plasma concentration with advancing age in pigs. The albumin concentration decreased by 17% with age in Fischer 344 rats, as previously reported in other studies [16,22,23].…”

Section: Discussionsupporting

confidence: 87%

“…Satterwhite and Boudinot [16] also obtained this result for Fischer 344 rats, but they reported that the microsomal protein content was approximately 63% lower in the old animals in comparison to that observed in the young rats.…”

Section: Discussionmentioning

confidence: 82%

“…In the present study, the total clearance of lerisetron in old rats was lower than that in adult and young rats. Since lerisetron is considered to be an intermediately metabolized drug, the decrease in CL observed for old rats may be attributed both to a reduction in hepatic blood flow (by 40-50%) or to a decrease in metabolic activity in the senescent rats [16]. On the other hand, the dependence of hepatic drug clear-ance of intermediately metabolized drugs on the plasma binding is not clear, and the results are conflicting, as previously reported for other intermediately extracted drugs like quinidine [17].…”

Section: Discussionmentioning

confidence: 99%

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Age-Related Changes in Pharmacokinetics and Pharmacodynamics of Lerisetron in the Rat: A Population Pharmacokinetic Model

Jauregizar

Quintana²,

Súárez³

et al. 2003

Gerontology

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Background: The importance of studying the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron – a new 5-hydroxytryptamine-3 (serotonin) receptor antagonist – comes from the facts that lerisetron will be administered to patients that are being treated with cytotoxic drugs and that the elderly frequently suffer from neoplastic diseases. Objective: The present study was designed to explore the effects of age on the pharmacokinetics and pharmacodynamics of lerisetron by using an aged rat model. A mixed-effects population study was carried out in order to analyze the sparse data and to create covariate models which could be used to derive dosage recommendations. Methods: Fischer 344 rats (n = 44) were divided into three groups, depending on their age: 5, 13, and 25 months. Blood samples were collected before administration of 200 µg/kg of lerisetron for measurements of albumin, α₁-acid glycoprotein, and unbound fraction of lerisetron. The lerisetron plasma concentrations were measured by high-performance liquid chromatography. A two-compartment model was fitted to the data using the nonlinear mixed-effects computer program WinNonMix. The population analysis was performed with the complete set of the collected data, and the potential sources of variability in the population parameters were investigated. Additionally, a pharmacodynamic study was performed. The effect of lerisetron (inhibition of the von Bezold-Jarisch reflex) was evaluated in young, adult, and senescent Fischer 344 rats. Results: The mean values of the individual Bayes estimates of the parameters showed a decrease in total clearance and distribution volume of the central compartment in old rats. The lerisetron free (unbound) fraction remained unchanged among the groups, and there were no significant differences in α₁-acid glycoprotein levels. The concentration-effect relationship was best described by a sigmoid E_max model. Since the drug concentration in plasma at half-maximal effect (EC₅₀) decreased in old rats, an increased sensitivity to the effect of lerisetron in old animals could be expected. Conclusion: Both pharmacokinetic changes (decreased volume of distribution and clearance and increased elimination half-life) and pharmacodynamic alterations (decrease in total and unbound EC₅₀) may be responsible for the different responses to lerisetron observed in old rats.

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