Plasma level monitoring of nasal salmon calcitonin in the rat by a heterogeneous two-site enzyme immunoassay.
The experimental and clinical effectiveness of nasal salmon calcitonin (SCT) for treatment of osteoporosis in humans has been well established, but none is known yet about the pharmacokinetic property in relation to therapeutic efficacy, especially when used in a therapeutic dose range. This preclinical study was designed to evaluate such a property, first of all in rats, using a novel heterogeneous two-site enzyme immunoassay that has allowed us to evaluate the pharmacokinetic property of parenteral SCT in rats due to the high sensitivity (the detection limit = 2 pg of SCT/ml of plasma). It was found that as early as 10 min after the nasal dosing of 1.25, 5, or 20 U/rat, the SCT immunoactivity became detectable in plasma and thereafter it waned rapidly with time. Hypocalcemia developed in a dose-dependent manner, but with a delay of approximately 20 min from the peak of the immunoactivity and lasted hours. The pharmacokinetic parameters measured for the doses (1.25, 5, and 20 U/rat) were as follows; the AUCs (pg.hr/ml) = 20.8, 89.0, and 189, and the MRTs (min) = 52, 54, and 45, respectively. The results appear to suggest: (1) the unexpected quick transfer of nasal SCT into and from the circulation, (2) a delayed onset of hypocalcemia and possibly its anti-osteopenic action, both of which may last longer, (3) that keeping the plasma SCT above the in vitro anti-osteoclastic level (approximately 1 pM) only for a few hours per 2 days would be enough for inducing the distinct anti-osteopenic effect in rats, and (4) the feasibility of designing the clinical study as to the pharmacokinetics and pharmacodynamics of nasal SCT on humans.
Nakamuta
H
H
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Kohno
T
T
Ichikawa
M
M
Hoshino
T
T
Watabe
K
K
Koida
M
M
D000281:Administration, Intranasal; D000700:Analgesics / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000517:prevention & control; D002116:Calcitonin / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006996:Hypocalcemia / Q000188:drug therapy; D007118:Immunoassay / Q000379:methods*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000700:Analgesics; C028815:salmon calcitonin; D002116:Calcitonin