Pharmacokinetics of a new proton pump inhibitor, YJA‐20379‐8, after intravenous and oral administration to spontaneously hypertensive rats and DOCA‐salt‐induced hypertensive rats

Abstract

The purpose of this study was to investigate the causes for the differences observed in the pharmacokinetics of YJA-20379-8 in 16-week-old spontaneously hypertensive rats (SHRs). To see if the hereditary characteristics of SHRs was the cause, 20 mg/kg of the drug was intravenously infused over 15 min and 50 mg/kg of the drug was orally administered to 6-week-old SHRs and 16-week-old SHRs and their age-matched control Kyoto-Wistar (KW) rats. Also to see if the hypertensive status itself was the cause, the same doses were administered to 16-week-old deoxycorticosterone acetate (DOCA) salt-induced hypertensive rats (DOCA-salt rats) and their age-matched control Sprague-Dawley rats. The areas under the plasma concentration-time curve from time zero to time infinity (for intravenous study) and to the last sampling time in plasma (for oral study) were significantly smaller after both intravenous and oral administration, and the total body clearances of the drug were significantly faster after intravenous administration to 6-week-old SHRs, 16-week-old SHRs, and 16-week-old DOCA-salt rats than those in their respective age-matched control rats. The above pharmacokinetic parameter changes in 16-week-old SHRs were due to both hereditary characteristic of SHRs and the hypertensive status itself.

Pharmacokinetics of mirodenafil and Its two metabolites, SK3541 and SK3544, in spontaneously or DOCA–salt‐induced hypertensive rats

“…The significantly greater Cl nr s of DA‐1131 in 6‐ and 16‐week‐old SHRs were due to increased kidney metabolism of DA‐1131 because of the considerably greater total renal dehydropeptidase‐1 activity 9. The significantly greater Cl nr of YJK‐20379‐8 in 16‐week‐old SHRs was due to both the hereditary characteristics of SHRs and the hypertensive state itself 10. The significantly greater Cl nr and unchanged AUC of intravenous DA‐8159 in 16‐week‐old SHRs were due to neither hereditary characteristics of SHRs nor due to the hypertensive state itself 11.…”

“…In other studies, spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate–salt‐induced hypertensive rats (DOCA–salt rats) have been employed as animal models for human primary (essential) and secondary hypertension, respectively 3, 4. The pharmacokinetics of benazeprilat 5, morphine 6, thiorphan 7, DA‐125, an analog of adriamycin 8, DA‐1131, a carbapenem antibiotic 9, YJA‐20379‐8, a new proton pump inhibitor 10, DA‐8159 (Zydena ® ; Udenafil) 11 and metoprolol 12 were compared in SHRs and their age‐matched control Kyoto–Wistar (KW) rats and/or DOCA–salt rats and their age‐matched control SD rats. However, comparable studies on mirodenafil have not been reported.…”