Study on the metabolic fate of catena-(S)-[mu-[N alpha-(3- aminopropionyl)histidinato(2-)-N1,N2,O:N tau]-zinc]. 1st communication: absorption, distribution, metabolism and excretion after single administration to rats.
Studies on the absorption, distribution, metabolism and excretion of 14C-Z-103 and 65Zn-Z-103 (catena-(S)-[mu-[N alpha-(3- aminopropionyl)histidinato(2-)-N1,N2,O:N tau]-zinc], CAS 107667-60-7) were performed after oral administration to rats. After oral administration of 14C-Z-103 and 65Zn-Z-103, the blood concentrations of 14C-radioactivity were 30- to 40-fold higher than those of 65Zn-radioactivity. The 14C-radioactivity showed a dose-dependent increase of Cmax and AUC values in the dose range from 13.1 mg/kg to 100 mg/kg, and remained longer in the blood. In contrast, no dose-dependent increase of AUC was observed with 65Zn-radioactivity, suggesting saturation of absorption at doses more than 30 mg/kg of 65Zn-Z-103. The major route of excretion of 14C-radioactivity was by excretion into the expired air, amounting to 38.8% of the administered dose, while the urinary and fecal excretions were low values at 4.1% and 13.3%, respectively. The radioactivity remaining in the carcass accounted for 39.3% of the dose. On the other hand, in the case of 65Zn-radioactivity, 85.0% of the administered dose was excreted into the feces and 10.5% of the dose remained in the carcass. Both 14C- and 65Zn-radioactivities were distributed to the whole body, while 14C-radioactivity showed higher concentrations in the body, and was retained longer than the 65Zn-radioactivity. When the plasma and the liver and kidney homogenates, from rats received 14C-Z-103, were treated with trichloroacetic acid (TCA), the radioactivities in the TCA-insoluble fraction increased as a function of time. Following the treatment of the homogenates with protease, the radioactivities in the TCA-insoluble fraction decreased. In vitro study was showed that L-carnosine of 14C-Z-103 added to the homogenates of liver and small intestine was metabolized to L-histidine. The results suggest that the remaining radioactivities in tissues and organs caused the incorporation of the metabolites of 14C-Z-103 into endogenous high molecular substances.
Sano
H
H
Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., Saitama, Japan.
Furuta
S
S
Toyama
S
S
Miwa
M
M
Ikeda
Y
Y
Suzuki
M
M
Sato
H
H
Matsuda
K
K
D000818:Animals; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002336:Carnosine / Q000378:metabolism / Q000031:analogs & derivatives; D004151:Dipeptides / Q000378:metabolism / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D006639:Histidine / Q000378:metabolism; D007408:Intestinal Absorption; D008297:Male; D009942:Organometallic Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D017967:Zinc Compounds; D015037:Zinc Radioisotopes
D001798:Blood Proteins; D004151:Dipeptides; D009942:Organometallic Compounds; D017967:Zinc Compounds; D015037:Zinc Radioisotopes; C061957:polaprezinc; D006639:Histidine; D002336:Carnosine