Differences in the Pharmacokinetics of 4-Amino-3-Chlorophenyl Hydrogen Sulfate, a Metabolite of Resatorvid, in Rats and Dogs

Jinno, Fumihiro; Takeuchi, Toshiyuki; Tagawa, Yoshihiko; Kondo, Takahiro; Itoh, Tomoo; Asahi, Satoru

doi:10.1124/dmd.111.043729

Cited by 3 publications

(10 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After i.v. administration of [phenyl ring‐U‐ 14 C]M‐III at a dose of 0.5 mg/kg, the concentration of M‐III in the plasma of rats and dogs at 5 min was 2.288 µg/ml (9.27 µmol/l) and 4.687 µg/ml (19.0 µmol/l), respectively . Since the binding ratio of M‐III to plasma protein was approximately 90%, the concentration of M‐III based on the free fraction in plasma was estimated to be 0.927 to 1.90 µmol/l.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggested that the species difference in the pharmacokinetics of M‐III could be mainly attributable to the renal excretion process. Moreover, the concentration of the radioactivity in the kidney of rats was higher than that in the plasma, whereas that of dogs was lower than that in the plasma . This result indicated the involvement of transporter(s) in the uptake of M‐III via the basolateral membrane of rat kidney.…”

Section: Introductionmentioning

confidence: 86%

“…Pharmacokinetic studies in rats and dogs indicated a fairly excellent metabolic stability of M‐III and the parent drug accounted for most of the radioactivity in the plasma and urine after i.v. administration of [ 14 C]M‐III . Therefore, the total radioactivity in all the samples was assumed to be derived only from [ 14 C]M‐III in this study.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, after i.v. administration of 14 C‐labeled M‐III (4‐amino‐3‐chloro[U‐ 14 C]phenyl hydrogen sulfate; [ 14 C]M‐III) in rats and dogs, persistence of M‐III was also observed in the plasma of dogs, whereas M‐III was rapidly eliminated from the plasma of rats . Since M‐III was mainly excreted in urine in unchanged form in both species, differences in the metabolic clearance could not cause this species difference.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Species differences of organic anion transporters involved in the renal uptake of 4‐amino‐3‐chlorophenyl hydrogen sulfate, a metabolite of resatorvid, between rats and dogs

Takeuchi

Jinno

Ebihara

et al. 2013

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

Previous studies on the metabolic fate of resatorvid (TAK-242) have shown that species differences in the pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate (M-III), a metabolite of TAK-242, between rats and dogs are mainly attributable to the urinary excretion process. In the present study, the renal uptake mechanism of M-III was investigated using kidney slices and Xenopus laevis oocytes expressing rat organic anion transporter 1 (rOat1; Slc22a6) and rOat3 (Slc22a8). The uptake of p-aminohippuric acid (PAH), a substrate for Oats, by kidney slices from rats and dogs increased at 37 °C and M-III inhibited the uptake. The initial uptake clearance of M-III by rat kidney slices was 0.295 and 0.0114 ml/min/g at 37 °C and 4 °C, respectively. The Eadie-Hofstee plot of M-III uptake at 37 °C revealed two-component transport processes with K(m) values being 6.48 and 724 µmol/l. The uptake was inhibited by probenecid (PBC), PAH and benzylpenicillin (PCG). In contrast, in dog kidney slices, the initial uptake clearance of M-III was 8.70 × 10(-3) and 9.00 × 10(-3) ml/min/g at 37 °C and 4 °C, respectively, and the uptake was not inhibited by PBC. Furthermore, rOat1- and rOat3-expressing oocytes mediated M-III uptake and the uptake was inhibited by PAH and PCG, respectively. These results suggest that rOat1 and rOat3 are responsible for the renal uptake of M-III in rats. Moreover, it is speculated that Oat(s) is unable to transport M-III in dogs and that the difference in the substrate recognition of Oat(s) contributes to the species difference in the pharmacokinetics of M-III between rats and dogs.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Species differences of organic anion transporters involved in the renal uptake of 4‐amino‐3‐chlorophenyl hydrogen sulfate, a metabolite of resatorvid, between rats and dogs

Takeuchi

Jinno

Ebihara

et al. 2013

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

show abstract

“…23 TAK-242 has been described extensively as a specific inhibitor of TLR4 signaling in vitro using murine peritoneal macrophages for cytokine read-out after LPS stimulation. 23 TAK-242 has been described extensively as a specific inhibitor of TLR4 signaling in vitro using murine peritoneal macrophages for cytokine read-out after LPS stimulation.…”

Section: Discussionmentioning

confidence: 99%

Toll-like Receptor 4 Inhibitor TAK-242 Treatment Does Not Influence Perfusion Recovery in Tissue Ischemia

Borne¹,

Bastiaansen²,

Vries

et al. 2014

Journal of Cardiovascular Pharmacology

View full text Add to dashboard Cite

Toll-like receptors (TLRs) are important in innate immune responses, which are crucial in collateral artery formation (arteriogenesis). TLR4⁻/⁻ mice undergoing hind limb ischemia show decreased perfusion recovery accompanied by an impaired infiltration of inflammatory cells. TLR antagonists are currently developed and tested with the objective to inhibit acute exacerbation of organ damaging immune responses. However, systemic inhibition of innate immune responses may negatively influence arteriogenesis. In this study, we evaluated if TLR4 inhibition by a potent TLR4 inhibitor (TAK-242) would negatively influence perfusion recovery in a mouse model for arteriogenesis. Whole blood from human and mouse origin was stimulated with the TLR4 ligand lipopolysaccharide following TAK-242 incubation. After stimulation, cellular TLR4 activation was measured using fluorescence-activated cell sorting and tumor necrosis factor alpha release was measured using enzyme-linked immunosorbent assay. Next, the effect of TAK-242 was tested in a mouse model for arteriogenesis on perfusion recovery. TLR4 responses measured by tumor necrosis factor alpha levels were inhibited by TAK-242 in human and mouse blood after long-term stimulation. TAK-242 attenuated TLR4 responses in vivo but did not inhibit perfusion recovery in mice. In conclusion, TAK-242 does not negatively influence perfusion recovery following hind limb ischemia despite its TLR4 inhibiting properties.

show abstract

TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice

Fang

Tang

Wang

et al. 2015

J Cereb Blood Flow Metab

154

109

View full text Add to dashboard Cite

Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.

show abstract

Differences in the Pharmacokinetics of 4-Amino-3-Chlorophenyl Hydrogen Sulfate, a Metabolite of Resatorvid, in Rats and Dogs

Abstract: ABSTRACT:The pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, M-III of resatorvid, in rats and dogs were investigated using

Cited by 3 publications

References 12 publications

Species differences of organic anion transporters involved in the renal uptake of 4‐amino‐3‐chlorophenyl hydrogen sulfate, a metabolite of resatorvid, between rats and dogs

Species differences of organic anion transporters involved in the renal uptake of 4‐amino‐3‐chlorophenyl hydrogen sulfate, a metabolite of resatorvid, between rats and dogs

Toll-like Receptor 4 Inhibitor TAK-242 Treatment Does Not Influence Perfusion Recovery in Tissue Ischemia

TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice

Contact Info

Product

Resources

About