Role of the lipid emulsion on an injectable formulation of lipophilic KW-3902, a newly synthesized adenosine A1-receptor antagonist.
KW-3902 (a newly synthesized adenosine A1-receptor antagonist) has potent diuretic and renal protective activities. We investigated the influence of the emulsion formulation on the pharmacokinetics of KW-3902 and its metabolite (M1) in rats using three different formulations, i.e., a lipid emulsion about 130 nm in diameter composed of egg yolk lecithin: soybean oil: oleic acid=1:1:0.048, a liposome about 100 nm in diameter composed of egg yolk lecithin, and a saline solution containing 1% (v/v) each of dimethyl sulfoxide and 1 N NaOH. There was no significant difference in the pharmacokinetic parameters of KW-3902 (elimination half-life (T1/2), area under the plasma concentration-time curves (AUC0-infinity), total body clearance (CL), mean residence time (MRT) and volume of distribution at steady-state (Vdss) and M1 (Cmax, T1/2, AUC0-infinity and MRT) after injection of these three dosage forms. Moreover, we investigated in vitro the binding of KW-3902 to blood components using these three formulations. KW-3902 was completely partitioned into the blood components regardless of its dosage form. These findings suggested that KW-3902 dissociated rapidly from the lipid emulsion or liposome in blood after injection and showed intrinsic pharmacokinetics of KW-3902 at doses of 0.1 and 1 mg/kg. Thus, the lipid emulsion formulation of KW-3902 was defined as a solvent, which was a vehicle for dissolving the drugs to prepare the injection, at its expected effective doses.
Hosokawa
Toshihito
T
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan. t.hosokawa@kyowa.co.jp
Yamauchi
Masahiro
M
Yamamoto
Yoshihiko
Y
Iwata
Kenji
K
Mochizuki
Harumi
H
Kato
Yasuki
Y
D000818:Animals; D002626:Chemistry, Pharmaceutical; D005217:Fat Emulsions, Intravenous / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D008854:Microscopy, Electron; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000097:blood / Q000378:metabolism; D014018:Tissue Distribution; D014970:Xanthines / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics
D005217:Fat Emulsions, Intravenous; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014970:Xanthines; C073525:rolofylline