Imperfection of Drug Therapy

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1 Dcrasd Nuclar Rcptor ctivity diats Downrgulation of Drug tabolizing s in Chronic Kidny Disas Through Epigntic Modulation Octobr 2, 214 Brad Urquhart, PhD ssistant Profssor Dpartmnt of Physiology and Pharmacology Dpartmnt of dicin (Nphrology, Clinical Pharmacology) Dpartmnt of Padiatrics Lawson Halth Rsarch Institut Dpartmnt of Physiology and Pharmacology Imprfction of Drug Thrapy Disas Gntics Environmnt Factors diating Drug Disposition bsorption Distribution tabolism Excrtion Yungt al. Kidny Intrnational (214) Chronic Kidny Disas (CKD) Prcnt of population Stag Dscription GFR (ml/min/1.72m 2 ) 1 Kidny damag with normal or GFR 2 Kidny damag with mild GFR Modrat GFR Svr GFR Kidny failur <15 or anuric Charactrizd by a progrssiv dclin in rnal function ovr tim. Major causs of CKD includ diabts and rnal vascular disas (including high blood prssur) CKD is stimatd to affct btwn 1.9 million and 2.3 million Canadians m J Kidny Dis. 211;57(3)(suppl 2):S32-S56 1

2 Drugs and CKD Patints with CKD tak 7-12 mdications concurrntly to control a varity of comorbiditis. Ths patints hav an incrasd incidnc of advrs drug vnts, oftn du to incrasd blood drug concntrations. Many drugs ar xcrtd by th kidny so GFR adjustd dosing in patints with CKD is common. Drug Elimination Dos CKD impact hpatic drug mtabolism? tabolism Rnal Bil Winkrs and Hath (25) Nat Rv Drug Discov. 4 (1) Cytochrom P45 diatd Drug tabolism 3 2D6 2C 2E1 1 Shimada t al. (1994) J. Pharmacol. Exp. Thr. 27 (1) Nuclar Rcptor and Epigntic Changs in 3 and 2C diatd tabolism in CKD. Hypothsis ltrd drug mtabolism in CKD is scondary to dcrasd nuclar rcptor binding to th 3 and 2C promotr which is associatd with histon modulation. Objctiv 1. To dtrmin nuclar rcptor binding in CKD. 2. To invstigat th pigntic modulation of hpatic drug mtabolizing nzyms in CKD. 3. To valuat urmic toxins that may downrgulat hpatic 3. 2

3 Nuclar Rcptors Gn On H4 Modifid from Huss t al ctivating Gn Off K4 R3 H4 XRE RN Pol II TT 3 Silncing K9 K27 2C * Srum Cratinin (µm) Control CKD Vlnosit al. (214) FSEB J 3

4 Vlnosit al. (214) FSEB J Vlnosit al. (214) FSEB J Vlnosit al. (214) FSEB J 4

5 Possibl chanism For Hpatic Drug tabolizing Down- rgulation in CKD. tabolomics CONTROL chanism? UREMI Hundrds of urmic toxins accumulat in kidny disas. Do any of thm accumulat in th livr? Snsitiv QTOF mass spctromtr: can quantify and idntify small molculs. pplication to drug toxicity : pharmacomtabolomics XEVO-G2-S Mass Spctromtr Control tabolomic Invstigation Homogniz in actonitril Scors Plot: Control vs. CKD 1 t[2]o CKD Control Chronic Kidny Disas -1 Homogniz in actonitril -2-3 UPLC-MS t[1]p EZinf o 2 - CKD ST-12 Rat Livr Ng Mod Control v s CKD (M2: OPLS-D) :3:1 (UTC-5) Hnnop, Vlnosi t al. unpublishd 5

6 EZinf o 2 - CKD ST-12 Rat Liv r Ng Mod Control vs CKD (M2: OPLS-D) :1:14 (UTC-5) 1/31/214 tabolomics of Livr Sampls in CKD Conclusions and Futur Dirctions p(corr)[1]p (Corrlation) S-Plot (Control = -1, CKD = 1) CONCLUSIONS PXR and HNF4α binding to 2C11 and 32 promotrs is dcrasd in CKD. Changs in histon actylation ar associatd with dcrasd 2C11 and 32 xprssion in CKD. FUTURE DIRECTIONS tabolomic invstigation to dtrmin which urmic toxins ar lvatd in th livr p[1]p (Loadings) cknowldgmnts Urquhart lab Dav Fr, MSc nzl Hnnop ndrw Kucy lvin Tiu Dr. Bn Thomson Tom Vlnosi ndrw Wong Collaborators Dr. Tom Nolin (Univrsity of Pittsburgh) Dr. ndrw Hous Linda shr, RN Tom Vlnosi, PhD Candidat David Fr, MSc Dr. Bn Thomson Rlativ Exprssion DMSO Indoxyl Sulfat * * Cocktail Vlnosi t al. unpublishd Cocktail: CMPF Cratinin P-Crsyl sulfat Indoxyl Sulfat Guanidinosuccinic acid Hippuric acid Indol-3-actic acid thylguanidin Ura 6

7 Possibl chanism For Hpatic Drug tabolizing Down- rgulation in CKD. Rlativ Exprssion (% Control) Normal Urmia * * Log [Indoxyl Sulfat] µm I CONTROL UREMI chanism? Indoxyl Sulfat? NO FBS dia FBS dia Vlnosi t al. unpublishd 7