SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase. II: In vitro and in vivo metabolism studies and pharmacokinetic extrapolation to man

Ward, Keith W.; Proksch, Joel W.; Gorycki, Peter D.; Yu, Chenggang; Ho, May Y. K.; Bush, Brian; Levy, Mark A.; Smith, Brian R.

doi:10.1080/00498250110100711

Cited by 15 publications

(9 citation statements)

References 15 publications

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“…In the present series of studies, evidence of non-linearity was noted for SB-242235 in both rat and monkey. The mechanism of this non-linearity was not evident, but is likely renal in nature, given the primarily renal elimination of SB-242235 (Ward et al 2002). Non-linear renal elimination may arise through several mechanisms (reviewed by Bonate et al 1998).…”

Section: Discussionmentioning

confidence: 96%

“…Systemic plasma clearance was high in the rat, but in the non-rodent species, SB-242235 demonstrated low to moderate clearance with plasma elimination half-lives >4 h. Oral bioavailability in each of the preclinical species was high. The high plasma clearance coupled with low ®rst-pass hepatic extraction in the rat suggested that clearance of SB-242235 was non-hepatic in nature; subsequent investigations have revealed renal elimination of unchanged compound to be the primary route of clearance for SB-242235 (Ward et al 2002). These pharmacokinetic data suggest that SB-242235 possesses dispositional properties conducive to further in vitro and in vivo investigation of the e ects of p38 inhibition, and may be an e ective oral agent for the treatment of human disease.…”

Section: Discussionmentioning

confidence: 97%

“…These pharmacokinetic data suggest that SB-242235 possesses dispositional properties conducive to further in vitro and in vivo investigation of the e ects of p38 inhibition, and may be an e ective oral agent for the treatment of human disease. A description of the pharmacokinetic behaviour of SB-242235 in man, as well as a detailed extrapolation exercise based in part on the present data, are presented separately (Fullerton et al 2000, Ward et al 2002.…”

Section: Discussionmentioning

confidence: 98%

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SB-242235, a selective inhibitor of p38 mitogenactivated protein kinase. I: Preclinical pharmacokinetics

et al. 2002

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1. SB-242235 (1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole) is a potent and selective p38 MAP kinase inhibitor that may be an effective therapy for cytokine-mediated diseases such as autoimmune or inflammatory diseases. The present studies were conducted to evaluate the pharmacokinetics of SB-242235 in several preclinical species, including rat, dog and monkey. 2. SB-242235 demonstrates generally favourable pharmacokinetic properties in all species examined. Systemic plasma clearance was high in rat, but in the non-rodent species SB-242235 demonstrated low to moderate clearance with plasma half-lives > 4h. Oral bioavailability in each preclinical species was high. In rat and monkey, SB-242235 demonstrated non-linear elimination kinetics that manifested as a decrease in clearance with increasing dose and apparent oral bioavailability > 100% at high oral doses. Furthermore, SB-242235 displayed concentration-dependent plasma protein binding over a concentration range of 1000-10,000 ng ml(-1). 3. In conclusion, SB-242235 demonstrates high oral bioavailability across the major preclinical species, and may thus be a useful tool compound for investigation of the role of p38 inhibition in various disease states. However, the observations of non-linear protein binding and disposition also suggest the need for caution in the design of and data interpretation from such studies.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

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SB-242235, a selective inhibitor of p38 mitogenactivated protein kinase. I: Preclinical pharmacokinetics

et al. 2002

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“…However, RWJ-67657, BIRB 796 BS, and SB-242235 are experimental drugs that have been used to inhibit p38 MAPK activity in preclinical studies and in an animal model of rat and monkey (10,11,56,83). In the future, it is possible that drugs such as these might be useful to modulate p38 MAPK activity in macrophages to promote phagocytosis, but this possibility awaits substantial further study as well as the elucidation of possible side effects.…”

Section: Discussionmentioning

confidence: 99%

Activation of p38 MAPKα by extracellular pressure mediates the stimulation of macrophage phagocytosis by pressure

Shiratsuchi¹,

Basson²

2005

American Journal of Physiology-Cell Physiology

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We have previously demonstrated that constant 20 mmHg extracellular pressure increases serumopsonized latex bead phagocytosis by phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages in part by inhibiting focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Because p38 MAPK is activated by physical forces in other cells, we hypothesized that modulation of p38 MAPK might also contribute to the stimulation of macrophage phagocytosis by pressure. We studied phagocytosis in PMA-differentiated THP-1 macrophages, primary human monocytes, and human monocyte-derived macrophages (MDM). p38 MAPK activation was inhibited using SB-203580 or by p38 MAPK␣ small interfering RNA (siRNA). Pressure increased phagocytosis in primary monocytes and MDM as in THP-1 cells. Increased extracellular pressure for 30 min increased phosphorylated p38 MAPK by 46.4 Ϯ 20.5% in DMSO-treated THP-1 macrophages and by 20.9 Ϯ 9% in primary monocytes (P Ͻ 0.05 each). SB-203580 (20 M) reduced basal p38 MAPK phosphorylation by 34.7 Ϯ 2.1% in THP-1 macrophages and prevented pressure activation of p38. p38 MAPK␣ siRNA reduced total p38 MAPK protein by 50 -60%. Neither SB-203580 in THP-1 cells and peripheral monocytes nor p38 MAPK siRNA in THP-1 cells affected basal phagocytosis, but each abolished pressure-stimulated phagocytosis. SB-203580 did not affect basal or pressure-reduced FAK activation in THP-1 macrophages, but significantly attenuated the reduction in ERK phosphorylation associated with pressure. p38 MAPK␣ siRNA reduced total FAK protein by 40 -50%, and total ERK by 10 -15%, but increased phosphorylated ERK 1.4 Ϯ 0.1-fold. p38 MAPK␣ siRNA transfection did not affect the inhibition of FAK-Y397 phosphorylation by pressure but prevented inhibition of ERK phosphorylation. Changes in extracellular pressure during infection or inflammation regulate macrophage phagocytosis by a FAKdependent inverse effect on p38 MAPK␣ that might subsequently downregulate ERK.force; inflammation; infection; leukocyte; mechanotransduction; signal transduction MONOCYTES AND MACROPHAGES are recruited to sites of inflammation and play critical roles in innate host defense mechanisms. Tissue pressure is often altered in association with inflammation or infection. Mechanical stimuli such as pressure are known to modulate cellular morphology and function in other cell types (7,38,39,73,79). We have previously reported that constant low extracellular pressure increases phagocytosis by phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 macrophages (67). Although focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) are activated by physical force caused by pressure in some other cell types (2,4,44,75,76,80), the effect of pressure on macrophage phagocytosis appears partially mediated by inhibition of a FAK-ERK signal pathway (67). Like ERK, the mitogen-activated protein kinase (MAPK) p38 is activated by various stress stimuli, including lipopolysaccharide (LPS) stimulation in macrophages and physical force...

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“…In conducting such extrapolation, one frequently used measure of predictive quality or extrapolation success is the degree of interspecies agreement (i.e., the r 2 value of the allometric linear regression); the correlation coefficient has also been used as a justification to exclude certain species from an extrapolation set (Chung et al, 1985;Brazzell et al, 1990;Efthymiopoulos et al, 1991;Cherkofsky, 1995;Feng et al, 1998;Kim et al, 1998;Sukbuntherng et al, 2001). Although previous investigations have demonstrated this idea to be incorrect for specific compounds (Ward et al, 2002), the present study demonstrates that an improved mathematical correlation coefficient does not signify an improved ability of allometric scaling to correctly predict human clearance on a more global basis. Additionally, the allometric exponents calculated were based on the three-species scaling of the present data contrast to the historical understanding of allometric exponents.…”

Section: Ward and Smithmentioning

confidence: 99%

A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

Ward¹,

Smith²

2004

Drug Metab Dispos

188

195

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ABSTRACT:This study was conducted to comprehensively survey the available literature on intravenous pharmacokinetic parameters in the rat, dog, monkey, and human, and to compare common methods for extrapolation of clearance, to identify the most appropriate species to use in pharmacokinetic lead optimization, and to ascertain whether adequate prospective measures of predictive success are currently available. One hundred three nonpeptide xenobiotics were identified with intravenous pharmacokinetic data in rat, dog, monkey, and human; both body weight-and hepatic blood flowbased methods were used for scaling of clearance. Allometric scaling approaches, particularly those using data from only two of the preclinical species, were less successful at predicting human clearance than methods based on clearance as a set fraction of liver blood flow from an individual species. Furthermore, commonly used prospective measures of allometric scaling success, including correlation coefficient and allometric exponent, failed to discriminate between successful and failed allometric predictions. In all instances, the monkey tended to provide the most qualitatively and quantitatively accurate predictions of human clearance and also afforded the least biased predictions compared with other species. Additionally, the availability of data from both common nonrodent species (dog and monkey) did not ensure enhanced predictive quality compared with having only monkey data. The observations in this investigation have major implications for pharmacokinetic lead optimization and for prediction of human clearance from in vivo preclinical data and support the continued use of nonhuman primates in preclinical pharmacokinetics.

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SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase. II: In vitro and in vivo metabolism studies and pharmacokinetic extrapolation to man

Cited by 15 publications

References 15 publications

SB-242235, a selective inhibitor of p38 mitogenactivated protein kinase. I: Preclinical pharmacokinetics

SB-242235, a selective inhibitor of p38 mitogenactivated protein kinase. I: Preclinical pharmacokinetics

Activation of p38 MAPKα by extracellular pressure mediates the stimulation of macrophage phagocytosis by pressure

A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

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