Nasal delivery of a vasopressin antagonist in dogs.
The dosage form (drop or spray) and site of administration (dorsal or ventral surface of the nostril) profoundly affect the distribution and clearance of a gamma-emitting 99mTc-labeled diethylenetriamine pentaacetic acid (99mTc-DTPA) solution in dogs. The slowest nasal clearance was observed for dorsally administered drops. Administration of drops to the ventral surface or sprays to either dorsal or ventral surface results in rapid clearance and little deposition in the turbinates. The octapeptide vasopressin antagonist, SKF 101926, was administered intravenously (0.3, 1.0, 3.0, and 10 micrograms/kg) and then on separate occasions intranasally (10, 25, and 50 micrograms/kg as a drop to the ventral surface) to four conscious, trained, female, water-loaded, vasopressin-infused dogs. SKF 101926 reversed the antidiuretic response to vasopressin after administration by either the intravenous or intranasal route in a dose-dependent fashion. Peak dilution of urine occurred within 50- to 60-min postdosing by both routes. Estimated doses to reduce vasopressin antidiuresis by 50% were 1.4 micrograms/kg intravenously and 23 micrograms/kg intranasally. After recovery to at least 70% of antidiuretic base line, and then administration of a second dose of SKF 101926 (3 micrograms/kg), subsequent dilution of urine osmolality was inversely related to the magnitude of the previously administered dose. It is concluded that the estimated relative effectiveness of intranasally administered SKF 101926 is 3-21%, compared with intravenous administration. Acute tachyphylaxis to repeated dosing was observed. The mechanism of the apparent tachyphylaxic response was not elucidated. No tachyphylaxis to less frequent (weekly) dosing was observed.
Liversidge
G G
GG
Department of Drug Delivery, Smith Kline, and French Laboratories, Swedeland, Pennsylvania 19479.
Wilson
C G
CG
Sternson
W L
WL
Kinter
L B
LB
D000281:Administration, Intranasal; D000336:Aerosols; D000818:Animals; D001127:Arginine Vasopressin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D001682:Biological Availability; D004285:Dogs; D004304:Dosage Forms; D005260:Female; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D009296:Nasal Cavity / Q000378:metabolism*; D009942:Organometallic Compounds; D004369:Pentetic Acid; D016284:Technetium Tc 99m Pentetate
D000336:Aerosols; D004304:Dosage Forms; D009942:Organometallic Compounds; D001127:Arginine Vasopressin; D004369:Pentetic Acid; C050890:1-((beta-mercapto-beta)beta cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-9-des-Gly-arginine vasopressin; D016284:Technetium Tc 99m Pentetate