Pharmacokinetics of 1alpha,25-dihydroxyvitamin D3 in normal mice after systemic exposure to effective and safe antitumor doses.
OBJECTIVE
Calcitriol, 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)) has potent antiproliferative effects and potentiates the antitumor activity of many other cytotoxic drugs. 1,25-D(3) plasma pharmacokinetic (PK) parameters associated with antitumor activity in experimental animal models are unknown. The objective of this study was to determine plasma calcitriol PK in normal mice at doses of calcitriol which are active in suppressing tumor growth.


METHODS
Plasma 1,25-D(3) PK were examined in normal C3H/HeJ mice after a single intraperitoneal dose of 0.125 or 0.5 microg 1,25-D(3)/mouse. PK blood samples were collected from groups of 5-9 mice at each time point up to 24 h after 1,25-D(3) administration. Plasma 1,25-D(3) concentrations were measured by radioimmunoassay. Plasma 1,25-D(3) concentration diurnal variation was determined in blood samples from untreated animals collected in the morning (9:00-11:00 a.m.) and in the evening (4:00-9:00 p.m.).


RESULTS
Median baseline plasma 1,25-D(3) concentration measured in the morning and in the evening were 0.082 ng/ml (CI 95%, 0.076-0.099) and 0.067 ng/ml (CI 95%, 0.058-0.075), respectively (p = 0.004). After 0.125 and 0.5 microg dosing, peak plasma 1,25-D(3) concentrations (Cp(max)) were 12.0 ng/ml (CI 95%, 10.8-12.6) and 41.6 ng/ml (CI 95%, 40.8-53.6), respectively. The corresponding areas under the curve (AUC(0->24 h)) were 47.0 (CI 95%, 43.2-51.1) and 128.0 (CI 95%, 127.0-130.0) ng.h/ml. No dose-related changes in time to Cp(max) and apparent total plasma clearance were observed.


CONCLUSIONS
These results demonstrate diurnal variation in baseline plasma 1,25-D(3) concentrations in mice. Plasma 1,25-D(3) PK in mice receiving doses that are effective in slowing tumor growth, inducing cell cycle arrest and apoptosis, and potentiating taxanes and platinum analogue antitumor activity are at least 5-10 times higher than those easily achieved and nontoxic in patients receiving high-dose intermittent oral therapy.
Muindi
Josephia R
JR
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. josephia.muindi@roswellpark.org
Modzelewski
Ruth A
RA
Peng
Yibing
Y
Trump
Donald L
DL
Johnson
Candace S
CS
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002117:Calcitriol / Q000493:pharmacokinetics*; D002120:Calcium Channel Agonists / Q000493:pharmacokinetics*; D004357:Drug Synergism; D051379:Mice; D008809:Mice, Inbred C3H; D011863:Radioimmunoassay
D000970:Antineoplastic Agents; D002120:Calcium Channel Agonists; D002117:Calcitriol