title: PKPD modelling to predict altered disposition of 1α,25-dihydroxyvitamin D3 in mice due to dose-dependent regulation of CYP27B1 on synthesis and CYP24A1 on degradation.
abstract: OBJECTIVE
  Concentrations of 1α,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], the active ligand of the vitamin D receptor, are tightly regulated by CYP27B1 for synthesis and CYP24A1 for degradation. However, the dose-dependent pharmacokinetic (PK)-pharmacodynamic (PD) relationship between these enzymes and 1,25(OH)2 D3 concentrations has not been characterized.
  
  
  METHODS
  The pharmacokinetics of 1,25(OH)2 D3 were evaluated after administration of single (2, 60 and 120 pmol) and repeated (2 and 120 pmol q2d ×3) i.v. doses to male C57BL/6 mice. mRNA expression of CYP27B1 and CYP24A1 was examined by quantitative PCR and 1,25(OH)2 D3 concentrations were determined by enzyme immunoassay.
  
  
  RESULTS
  CYP27B1 and CYP24A1 changes were absent for the 2 pmol dose and biexponential decay profiles showed progressively shorter terminal half-lives with increasing doses. Fitting with a two-compartment model revealed decreasing net synthesis rates and increasing total clearances with dose, consistent with a dose-dependent down-regulation of renal CYP27B1 and the induction of renal/intestinal CYP24A1 mRNA expression. Upon incorporation of PD parameters for inhibition of CYP27B1 and induction of CYP24A1 to the simple two-compartment model, fitting was significantly improved. Moreover, fitted estimates for the 2 pmol dose, together with the PD parameters as modifiers, were able to predict profiles reasonably well for the higher (60 and 120 pmol) doses. Lastly, an indirect response model, which considered the synthesis and degradation of enzymes, adequately described the PK and PD profiles.
  
  
  CONCLUSIONS
  The unique PK of exogenously administered 1,25(OH)2 D3 led to changes in PD of CYP27B1 and CYP24A1, which hastened the clearance of 1,25(OH)2 D3 .
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Holly P
authors.initials: HP
authors.lastname: Quach
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Qi J
authors.initials: QJ
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Chow
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stacie Y
authors.initials: SY
authors.lastname: Hoi
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D014807:Vitamin D / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism*
chemical_list: C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase
references.citation: Drug Metab Dispos. 2000 Feb;28(2):224-35
references.pmid: 10640522
references.citation: Arch Biochem Biophys. 2000 Sep 1;381(1):143-52
references.pmid: 11019830
references.citation: Steroids. 2001 Mar-May;66(3-5):391-8
references.pmid: 11179748
references.citation: Clin Pharmacol Ther. 2001 Sep;70(3):210-6
references.pmid: 11557908
references.citation: Nephrol Dial Transplant. 2002 May;17(5):829-42
references.pmid: 11981071
references.citation: Mol Cancer Ther. 2002 Aug;1(10):821-9
references.pmid: 12492115
references.citation: Drug Metab Dispos. 2003 May;31(5):510-8
references.pmid: 12695336
references.citation: Cell Calcium. 2003 May-Jun;33(5-6):497-507
references.pmid: 12765695
references.citation: Oncology. 2004;66(1):62-6
references.pmid: 15031600
references.citation: Biochemistry. 1972 Nov 7;11(23):4251-5
references.pmid: 4342902
references.citation: J Pharmacokinet Biopharm. 1974 Apr;2(2):123-48
references.pmid: 4427218
references.citation: J Biol Chem. 1978 Jun 10;253(11):3804-9
references.pmid: 649607
references.citation: J Clin Invest. 1984 Dec;74(6):2136-43
references.pmid: 6549016
references.citation: Am J Physiol. 1987 Nov;253(5 Pt 2):F1015-9
references.pmid: 3688232
references.citation: Steroids. 1987 Jan-Mar;49(1-3):29-53
references.pmid: 2842896
references.citation: Am J Physiol. 1989 May;256(5 Pt 1):E686-91
references.pmid: 2785765
references.citation: Biochem J. 1989 Aug 15;262(1):173-80
references.pmid: 2818561
references.citation: Am J Kidney Dis. 1990 Aug;16(2):126-32
references.pmid: 2382648
references.citation: Kidney Int. 1990 Nov;38(5):857-61
references.pmid: 2266669
references.citation: Clin Nephrol. 1991 Feb;35(2):72-7
references.pmid: 2019017
references.citation: Biochem Pharmacol. 1991 Jun 1;41(11):1601-6
references.pmid: 2043150
references.citation: J Biol Chem. 1992 Jul 5;267(19):13757-62
references.pmid: 1618870
references.citation: Clin Endocrinol (Oxf). 1992 Jul;37(1):17-27
references.pmid: 1424188
references.citation: J Pharmacokinet Biopharm. 1993 Aug;21(4):457-78
references.pmid: 8133465
references.citation: Biochem Pharmacol. 1994 Nov 29;48(11):2081-90
references.pmid: 7802698
references.citation: J Bone Miner Res. 1995 Aug;10(8):1148-57
references.pmid: 8585417
references.citation: J Pharmacokinet Biopharm. 1996 Dec;24(6):611-35
references.pmid: 9300353
references.citation: Drug Chem Toxicol. 1997 Nov;20(4):329-44
references.pmid: 9433662
references.citation: Physiol Rev. 1998 Oct;78(4):1193-231
references.pmid: 9790574
references.citation: Clin Cancer Res. 1999 Jun;5(6):1339-45
references.pmid: 10389917
references.citation: Physiol Rev. 2005 Jan;85(1):373-422
references.pmid: 15618484
references.citation: Br J Pharmacol. 2013 Dec;170(8):1652-75
references.pmid: 24528240
references.citation: Br J Pharmacol. 2013 Dec;170(8):1797-867
references.pmid: 24528243
references.citation: Gastroenterology. 2014 Apr;146(4):1048-59
references.pmid: 24365583
references.citation: J Neurosci. 2014 May 21;34(21):7091-101
references.pmid: 24849345
references.citation: Endocrinology. 2005 Feb;146(2):825-34
references.pmid: 15498883
references.citation: Nucleic Acids Res. 2007;35(8):2734-47
references.pmid: 17426122
references.citation: Cancer Chemother Pharmacol. 2008 Oct;62(5):881-91
references.pmid: 18246349
references.citation: Nephrol Dial Transplant. 2008 Nov;23(11):3479-84
references.pmid: 18556746
references.citation: Drug Metab Pharmacokinet. 2009;24(1):16-24
references.pmid: 19252333
references.citation: Biopharm Drug Dispos. 2009 Nov;30(8):457-75
references.pmid: 19753549
references.citation: Br J Pharmacol. 2010 Aug;160(7):1573-6
references.pmid: 20649560
references.citation: Br J Pharmacol. 2010 Aug;160(7):1577-9
references.pmid: 20649561
references.citation: Clin Cancer Res. 2011 Feb 15;17(4):817-26
references.pmid: 21169243
references.citation: J Pharmacol Exp Ther. 2011 Jun;337(3):846-59
references.pmid: 21421739
references.citation: Cell Biochem Funct. 2012 Aug;30(6):445-56
references.pmid: 22528806
references.citation: Cancer Chemother Pharmacol. 2013 May;71(5):1173-82
references.pmid: 23435876
references.citation: Am J Physiol Endocrinol Metab. 2013 May 1;304(9):E977-89
references.pmid: 23482451
references.citation: Nucleic Acids Res. 2014 Jan;42(Database issue):D1098-106
references.pmid: 24234439
references.citation: Br J Pharmacol. 2013 Dec;170(8):1607-51
references.pmid: 24528239