Pharmacokinetics of RK-28 (a new radiosensitizer) and pharmaceutical design of a suppository form using rats.
The pharmacokinetics of RK-28, a new hypoxic cell radiosensitizer, was studied in rats following its intravenous, intraportal, oral, and rectal administration. The pharmaceutical design of an RK-28 suppository form was also examined. After intravenous injection, RK-28 was rapidly removed from the plasma (biological half-life of 17 min) and its area under the curve (AUC) was proportional to the amount of RK-28 administered. The absolute bioavailability of RK-28 was 59.7% for intraportal administration and 36.9% for oral administration. Following oral administration of RK-28, it seems likely that specific acid-catalyzed decomposition of RK-28 takes place in the stomach and then the absorbed RK-28 undergoes first-pass metabolism in the liver. When "solidified RK-28 suppository," made by solidifying molten RK-28, was inserted into the rectum, hepatic first-pass metabolism could be avoided substantially. The resulting absolute bioavailability of RK-28 increased to 75%. Furthermore, "RK-28 emulsion suppository," prepared by emulsifying RK-28 with 1-hexadecanol and hydrogenated castor oil (HCO 60) at 80 degrees C, showed a plasma concentration-time curve very suitable for radiation therapy; the maximum plasma concentration was attained 30 min after rectal administration and then decreased within a short period. Administration of "RK-28 emulsion suppository," resulted in an absolute bioavailability of 76%.
Kim
N S
NS
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Umejima
H
H
Miyata
K
K
Okubo
M
M
Goto
S
S
Kato
T
T
Mikami
Y
Y
Sagitani
H
H
Inoue
H
H
D000284:Administration, Oral; D000285:Administration, Rectal; D000818:Animals; D001682:Biological Availability; D004304:Dosage Forms; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004355:Drug Stability; D006207:Half-Life; D007275:Injections, Intravenous; D008297:Male; D008920:Misonidazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013488:Suppositories
D004304:Dosage Forms; D011838:Radiation-Sensitizing Agents; D013488:Suppositories; C047778:1-(4'-hydroxy-2'-butenoxy)methyl-2-nitroimidazole; D008920:Misonidazole