Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats, guinea-pigs, beagles and rhesus monkeys

Yoshimura, Tsutomu; Tanaka, Shigeru; Sakurai, Hideki; Nagai, Yoshitaka; Yamada, Katsushi; Katayama, Satoshi; Abe, S.; Yamatsu, Isao

doi:10.3109/00498259109039502

Cited by 4 publications

(3 citation statements)

References 10 publications

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“…Similarly, the glucuronide of a lipoxygenase inhibitor (E6080) has been reported as a compound exhibiting a species difference in excretion route (Yoshimura et al 1991). Urinary excretion of the E6080 glucuronide accounted for 68.4% of dose in monkeys, but only 0.5% of dose in rats, in which the glucuronide was predominantly excreted in bile (42.5% of dose).…”

Section: Discussionmentioning

confidence: 98%

“…The lack of dose proportionality in AUC is likely due to reabsorption of KW-4490 excreted into bile from the intestinal tract. When CL R was compared with glomerular filtration rate (GFR) of unbound KW-4490, estimated from creatinine clearance data (rats ¼ 0.432 and monkeys ¼ 0.120-0.142 l h À1 kg À1 ) (Yoshimura et al 1991) and f p of KW-4490, CL R in rats was less than f p ÁGFR (0.159 l h À1 kg À1 ), whereas CL R in monkeys was more than f p ÁGFR (0.00912-0.0108 l h À1 kg À1 ). These results indicate that renal tubular secretion contributes greatly to urinary excretion of KW-4490 in monkeys, but that large amounts of excreted KW-4490 are reabsorbed across the renal tubules in rats.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor: Difference in excretion of KW-4490 and acylglucuronide metabolites between rats and cynomolgus monkeys

et al. 2008

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1. The pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor, were investigated in rats and monkeys. After oral administration, KW-4490 was rapidly absorbed, and then its plasma concentrations apparently declined with half-lives of approximately 5 h in rats and 3.5 h in cynomolgus monkeys; however, a number of secondary peaks were apparent in the profiles for both species. The plasma pharmacokinetics of KW-4490 were comparable between rats and monkeys. 2. After oral administration, KW-4490 was mainly eliminated by metabolism to acylglucuronides and renal excretion in the unchanged form. KW-4490 acylglucuronides were found in monkey but not rat urine. In rats, KW-4490 acylglucuronides were excreted only in bile. Although the pathway of excretion of acylglucuronides differed between rats and monkeys, cumulative excretion in the two animals was very similar, as expected from comparable hepatic clearance for glucuronidation in rat and monkey liver microsomes. 3. The glomerular filtration rate of unbound KW-4490 indicated that renal tubular secretion was significant in monkeys, whereas reabsorption was significant in rats. These species differences in urinary excretion of KW-4490 and its acylglucuronide metabolites are most likely due to substrate specificity of active transporters in rat and monkey kidney.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor: Difference in excretion of KW-4490 and acylglucuronide metabolites between rats and cynomolgus monkeys

et al. 2008

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“…This species difference in excretion may reflect differences in urinary metabolite composition. Species variations have been reported in the threshold molecular weight for biliary excretion [4,5] and may contribute to species differences in the main excretion route. 14 C-NS-7 showed no marked species difference for serum protein binding in the rats, dogs, monkeys and humans, and specific binding to any of the representative human serum proteins.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of the New Pyrimidine Derivative NS-7, a Novel Na+/Ca2+ Channel Blocker

Nonaka

Tsujioka

Tougou

et al. 2011

Arzneimittelforschung

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Plasma concentration profiles and excretion were investigated after a single intravenous injection of 14C-NS-7 (4-(fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride, CAS 178429-67-9), a novel Na+/Ca2+ channel blocker, to rats, dogs and monkeys. Plasma protein binding of this drug was determined in vitro and in vivo. AUC0-infinity values for radioactivity and NS-7 after the intravenous administration of 14C-NS-7 to male rats increased with the dose, namely from 0.04 to 5 mg/kg (radioactivity) and from 0.2 to 5 mg/kg (NS-7), indicating the linearity of the drug's pharmacokinetics. Plasma concentrations of the unchanged drug after the intravenous injection of 0.2 mg/kg 14C-NS-7 decreased biexponentially, respective t1/2 beta values being 15.9 h in the male and 22.4 h in the female rats. The t1/2 beta values difference in the males and females might be due to sex differences in NS-7 metabolism. Urinary and fecal excretions of radioactivity within 168 h of administration were 33.0 and 61.4% of the dose in the male and 35.0 and 53.2% in the female rats. No radioactivity was detected in air exhaled from the males and females collected for 168 h after NS-7 administration. Within 24 h of administration, respective biliary excretions for the male and female rats were 26.1 and 11.9% of the dose. Of this excreted radioactivity, 34.9% was reabsorbed in the males. NS-7 plasma concentrations decreased biexponentially after intravenous administration of 0.2 mg/kg 14C-NS-7 to dogs and monkeys. The elimination half-life was 18 h for the dogs and 9.52 h for the monkeys. Urinary and fecal excretions of radioactivity within 168 h of administration were 24.2 and 70.0% of the dose for the dogs, and 63.3 and 24.8% for the monkeys. These species differences in excretion may be due to differences in urinary metabolite compositions. In vitro protein binding of NS-7 showed no marked species differences and was independent of the NS-7 concentration. Binding of 14C-NS-7 in the sera of rats, dogs, monkeys and humans was 90.7%, 73.5% 79.0% and 87.1%, respectively. Binding to human serum albumin, alpha 1-acid glycoprotein and lipoprotein was 56.2%, 45.4% and 79.5%, in the range of 4-40 ng/ml. In vivo binding in rat serum 5 min, 6 h and 24 h after the intravenous injection of 14C-NS-7(0.2 mg/kg) ranged from 89.6 to 90.6%.

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Expression of glutathione S-transferases Ya, Yb1, Yb2, Yc1 and Yc2 and microsomal epoxide hydrolase genes by thiazole, benzotbiazole and benzothiadiazole

Kim

Cho

1996

Biochemical Pharmacology

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Metabolism and excretion of a new 5-lipoxygenase inhibitor in rats, guinea-pigs, beagles and rhesus monkeys

Cited by 4 publications

References 10 publications

Pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor: Difference in excretion of KW-4490 and acylglucuronide metabolites between rats and cynomolgus monkeys

Pharmacokinetics and metabolism of KW-4490, a selective phosphodiesterase 4 inhibitor: Difference in excretion of KW-4490 and acylglucuronide metabolites between rats and cynomolgus monkeys

Pharmacokinetics of the New Pyrimidine Derivative NS-7, a Novel Na+/Ca2+ Channel Blocker

Expression of glutathione S-transferases Ya, Yb1, Yb2, Yc1 and Yc2 and microsomal epoxide hydrolase genes by thiazole, benzotbiazole and benzothiadiazole

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