Pharmacokinetics and disposition of CS-8958, a long-acting prodrug of the novel neuraminidase inhibitor laninamivir in rats.
CS-8958, a prodrug of laninamivir (R-125489), is currently under development as an inhaled anti-influenza drug. In this study, the pharmacokinetics and disposition of CS-8958 were characterized in rats. After intratracheal administration of 14C-CS-8958, radioactivity was retained over long periods in the target tissues (trachea and lung) as its active metabolite R-125489 - 19.12% of the dose was retained in the lung at 24 h. After intratracheal administration of CS-8958, plasma R-125489 concentration was slowly eliminated, and its half-life (14.1 h) was considerably longer than that after intravenous administration of R-125489. The radioactivity of intratracheally administered 14C-CS-8958 was mainly excreted into the urine (67.5% of dose), and this excretion lasted over long periods. R-125489 accounted for most of the urinary radioactivity recovered after 24 h. These results demonstrated that CS-8958 administered intratracheally to rats was converted/hydrolysed to R-125489 in the target tissues, and that the R-125489 was slowly excreted into the urine via an absorption rate-limiting process. Such distinctive pharmacokinetics attributed to the slow release of R-125489 suggests the potential for a long-acting anti-influenza drug.
Koyama
K
K
Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan. koyama.kumiko.hv@daiichisankyo.co.jp
Takahashi
M
M
Nakai
N
N
Takakusa
H
H
Murai
T
T
Hoshi
M
M
Yamamura
N
N
Kobayashi
N
N
Okazaki
O
O
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001646:Bile / Q000737:chemistry; D002855:Chromatography, Thin Layer; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D005243:Feces / Q000737:chemistry; D006146:Guanidines; D008297:Male; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D011714:Pyrans; D011851:Radioactivity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012794:Sialic Acids; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D014020:Tissue Extracts; D053243:Zanamivir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000998:Antiviral Agents; C546919:CS 8958; D004791:Enzyme Inhibitors; D006146:Guanidines; D011355:Prodrugs; D011714:Pyrans; D012794:Sialic Acids; D014020:Tissue Extracts; C546918:laninamivir; D009439:Neuraminidase; D053243:Zanamivir