Determination of the bioavailability and biodistribution of a single dose of oral cholecalciferol/Calcirol® soft gelatin capsule by pharmacoscintigraphy- CalSci study
Keywords:Bioavailability, Biodistribution, Calcirol®, Cholecalciferol, Pharmacokinetics, Pharmacoscintigraphy
Background: It is required to study the bioavailability and biodistribution of specific cholecalciferol formulation before prescribing. Pharmacoscintigraphy is an established radiological-imaging technique that is used to map various drug formulations as they traverses the human body (biodistribution) in real-time. We evaluated the bioavailability and biodistribution pattern, transit time, and gastrointestinal clearance of a single dose of Calcirol® soft gelatin capsule 60,000 IU [an oral cholecalciferol (vitamin D) formulation] using pharmacoscintigraphy.
Methods: Six male healthy adult volunteers were administered a single oral dose of Calcirol® soft gelatin capsule labelled with technetium-99m. Post-dosing, serial venous blood samples were collected till day 27 for the estimation of the plasma levels of 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol levels. Different pharmacokinetic parameters were calculated. Sequential static gamma imaging was performed to evaluate the biodistribution of Calcirol® soft gelatin capsule. Descriptive statistics was used. Various pharmacokinetic parameters were calculated from the concentration-time curves. Statistical analysis was carried out using Student’s t-test. Suitable multivariate analysis was performed based on the distribution of data. All statistical analyses were performed using SAS® Software (v 9.4).
Results: The overall absorption of Calcirol® soft gelatin capsule was 93.23%, which was fully from the small intestine. It led to achieving a sufficient level of 25-hydroxycholecalciferol (>60 ng/ml) within 6 hours of oral intake. The levels of plasma 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol increased (maximum around 6 and 18 days, respectively). The small intestinal residence time was around 16 hours. No adverse event was noted.
Conclusions: This was the first pharmacoscintigraphy study in the world which demonstrated the favourable bio-distribution of the Calcirol softgels supporting its role in vitamin D supplementation.
Nair R, Maseeh A. Vitamin D: The “sunshine” vitamin. J Pharmacol Pharmacother. 2012;3(2):118-26.
Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005;289:F8-28.
Golzarand M, Shab-Bidar S, Koochakpoor G, Speakman JR, Djafarian K. Effect of vitamin D3 supple-mentation on blood pressure in adults: An updated meta-analysis. Nutr Metab Cardiovasc Dis. 2016;26:663-73.
Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the calcium and vitamin D for diabetes mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011;94:486-94.
Mirhosseini N, Rainsbury J, Kimball SM. Vitamin D supplementation, serum 25(OH)D concentrations and cardiovascular disease risk factors: a systematic review and meta-analysis. Front Cardiovasc Med. 2018;5:87.
Ben-Shoshan M, Amir S, Dang DT, Dang LH, Weisman Y, Mabjeesh NJ. 1alpha,25-dihydroxyvitamin D3 (Calcitriol) inhibits hypoxia-inducible factor-1/vascular endothelial growth factor pathway in human cancer cells. Mol Cancer Ther. 2007;6:1433-9.
Umar M, Sastry KS, Chouchane AI. Role of vitamin D beyond the skeletal function: a review of the mo-lecular and clinical studies. Int J Mol Sci. 2018;19.
Foroozanfard F, Jamilian M, Bahmani F, Talaee R, Talaee N, Hashemi T, et al. Calcium plus vitamin D supplementation influences biomarkers of inflammation and oxidative stress in overweight and vitamin D-deficient women with polycystic ovary syndrome: a randomized double-blind placebo-controlled clinical trial. Clin Endocrinol. 2015;83:888-94.
Sintzel MB, Rametta M, Reder AT. Vitamin D and multiple sclerosis: a comprehensive review. Neurol Ther. 2018;7:59-85.
Mostafa WZ, Hegazy RA. Vitamin D and the skin: Focus on a complex relationship: a review. J Adv Res. 2015;6:793-804.
Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, Jones G. Vitamin D toxicity-a clinical perspective. Front Endocrinol. 2018;9:550.
Davis SS, Hardy JG, Newman SP, Wilding IR. Gamma scintigraphy in the evaluation of pharmaceutical dosage forms. Eur J Nucl Med. 1992;19:971-86.
Marwaha RK, Dabas A. Bioavailability of nanoemulsion formulations versus conventional fat soluble preparations of cholecalciferol (D3)- an overview. J Clin Orthop Trauma. 2019;10:1094-6.
Borel P, Caillaud D, Cano NJ. Vitamin D bioavailability: state of the art. Crit Rev Food Sci Nutr. 2015;55:1193-205.
Marwaha RK, Dev T, Mittal A, Mani K, Narang A, Arora P, et al. A randomised controlled trial comparing the efficacy of micellized and fat-soluble vitamin D3 supplementation in healthy adults. Br J Nutr. 2019;121(8):859-65.
Jain S, Dani P, Sharma RK. Pharmacoscintigraphy: a blazing trail for the evaluation of new drugs and deliv-ery systems. Crit Rev Ther Drug Carrier Syst. 2009;26(4):373-426.
Thombre AG, Shamblin SL, Malhotra BK, Connor AL, Wilding IR, Caldwell WB. Pharmacoscintigraphy studies to assess the feasibility of a controlled release formulation of ziprasidone. J Control Rel. 2015;213:10-7.
Kenyon CJ, Brown F, McClelland GR, Wilding IR. The use of pharmacoscintigraphy to elucidate food effects observed with a novel protease inhibitor (saquinavir). Pharm Res. 1998;15:417-22.
Wilding IR, Coupe AJ, Davis SS. The role of gamma-scintigraphy in oral drug delivery. Adv Drug Deliv Rev. 2001;46:103-24.
Stöcklin E, Eggersdorfer M. Vitamin D, an essential nutrient with versatile functions in nearly all organs. Int J Vitam Nutr Res. 2013;83:92-100.
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53-8.
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-30.
Edward M, Cole Z, Harvey N, Cooper C. The global epidemiology of vitamin D status. J Aging Res Clin Pract. 2014;3:148-58.
Hossein-Nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc Mayo Clin. 2013;88:720-55.
Van der Pligt P, Willcox J, Szymlek-Gay EA, Murray E, Worsley A, Daly RM. Associations of maternal vitamin D deficiency with pregnancy and neonatal complications in developing countries: a systematic review. Nutrients. 2018;10:e640.
Holick MF. The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord. 2017;18:153-65.
de Boer IH, Levin G, Robinson-Cohen C, Biggs ML, Hoofnagle AN, Siscovick DS, et al. Serum 25-hydroxyvitamin D concentration and risk for major clinical disease events in a community-based population of older adults: a cohort study. Ann Intern Med. 2012;156(9):627-34.
Lhamo Y, Chugh PK, Tripathi CD. Vitamin D supplements in the Indian market. Indian J Pharm Sci. 2016;78(1):41.
Maurya VK, Aggarwal M. Factors influencing the absorption of vitamin D in GIT: an overview. J Food Sci Technol. 2017;54:3753-65.