Pharmacokinetics of DA-125, a new anthracycline, after intravenous administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats.
Pharmacokinetic parameters-including tissue distribution, biliary excretion, and urinary excretion of M1-M4-were compared after an intravenous administration of DA-125 (a new anthracycline derivative; 20 mg/kg body weight) to male spontaneously hypersensitive rats (SHRs) at 16 weeks (an animal model for human primary hypertension) and at 6 weeks (corresponding to the early phase of the development of hypertension, at which time blood pressure remains within the normotensive range) of age and their age-matched control Kyoto-Wistar rats, and male deoxycorticosterone acetate-salt-induced Sprague-Dawley rats (DOCA-salt rats, an animal model for human secondary hypertension) at 16 weeks of age and their age-matched control Sprague-Dawley rats. Mean plasma concentrations of both M2 and M4, and the resultant area under the plasma concentration-time curve from time 0 to last measured time [AUCT; M2 (68.9 vs. 29.3 micrograms-min/ml) and M4 (53.4 vs. 33.4 micrograms-min/ml)], increased significantly in SHRs at 16 weeks of age, compared with their control rats. Similar results were also obtained from DOCA-salt rats at 16 weeks of age, compared with their control rats. However, values were not significantly different between SHRs at 6 weeks of age and their control rats. Previous data indicated that the significant increase in plasma concentrations and the resultant AUCT values of both M2 and M4 in SHRs at 16 weeks of age were due to the hypertension state itself, and not to any hereditary characteristics of the SHRs. The significantly increased plasma concentrations and the resultant AUCT values of M2 in both SHRs and DOCA-salt rats at 16 weeks of age were due to the significantly decreased biliary excretion of M2 and possibly to the increased amount of aldo-keto reductase in the liver. However, the increase in the two aforementioned pharmacokinetic parameters in the case of M4 were possibly due solely to the increased amount of aldo-keto reductase in the liver.
Yoon
E J
EJ
College of Pharmacy, Seoul National University, South Korea.
Shim
H J
HJ
Lee
J J
JJ
Lee
S D
SD
Kim
W B
WB
Yang
J
J
Lee
M G
MG
D000367:Age Factors; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000493:pharmacokinetics*; D001646:Bile / Q000737:chemistry; D003900:Desoxycorticosterone; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000378:metabolism* / Q000652:urine; D008099:Liver / Q000201:enzymology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride
D000903:Antibiotics, Antineoplastic; C090816:7-O-(2,6-Dideoxy-2-fluoro-alpha-talopyranosyl)adriamycinone- 14-beta-alaniate hydrochloride; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase