Effects of Enzyme Inducers in Therapeutic Efficacy of Rosiglitazone: An Antidiabetic Drug in Albino Rats

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1 Asin J. Exp. Si., Vol. 21, No. 2, 2007, Effets of Enzyme Inuers in Therpeuti Effiy of Rosiglitzone: An Antiieti Drug in Alino Rts Ann Chursi,#* P.K. Krr** A. S. Mnn* & M.D. Khry* * Deprtment of Phrmeutil Sienes, Dr. H.S. Gour University, Sgr (M.P.) ; Ini ** Deprtment of Phrmy, Annmli University, Annmli Ngr (TN); Ini Astrt : The effet of enzyme inuers on therpeuti effiy of Rosiglitzone (n ntiieti rug) ws evlute y using lloxn inue ieti rts. The results exhiit the omine minstrtion of enzyme inuers like rifmpiin, phenoritone n phenytoin with Rosiglitzone ws ontrinite. The purpose of the stuy revels tht if Rosiglitzone rug omine with si enzyme inuers then therpeuti effiy of Rosiglitzone eing ltere. Beuse enzyme inuers inue ytohrome P450 y enhning the rte of its synthesis n/or reuing the rte of egrtion. Therefore, omine ministrtion of enzyme inuers with Rosiglitzone is not visle. Sine the hypoglyemi effet of the rug is reue. The results exhiit tht omine ministrtion of enzyme inuers with Rosiglitzone ws ontrinite. Key wors : Rosiglitzone, lloxn, phenytoin, Rifmpiin, phenoritone Introution : Rosiglitzone n ntiieti thizoliine tegory of rugs linilly erese insulin resistne in musles n liver, whih enhnes gluose utiliztion n ereses hepti gluose output with the moern pproh of keeping loo sugr level uner ontrol in ptients with type-ii ietes (NIDDM). Moleulr tions of these gents is known tht they in to n tivte nuler reeptor peroxisome prolifertor tivte reeptor gmm (PPAR- ) tht is present in mny insulin sensitive tissues. PPAR- regultes trnsription of insulin responsive genes tht influene gluose n lipi metolism. When enzyme inuers suh s phenytoin, phenoritone n rifmpiin re tken onurrently with orl ntiietis, the therpeuti effiy my get ltere s enzyme inuers inues ytohrome P450 y enhning the rte of its synthesis n/or reuing the rte of egrtion (Bl n Dnhih, 2001). So the present work els with the effet of ove mentione enzyme inuers on therpeuti effiy of Rosiglitzone. Mterils n Methos : Swiss lino rts ( gm) rought to Centrl Animl House (Reg.No.160/ 1999/CPCSEA) Annmli University, Annmli ngr, Tmilnu were use throughout the stuy. Animl were house in # Corresponing uthor : Ann Chursi, Deprtment of Phrmeutil Sienes, Dr. H.S. Gour University, Sgr (M.P.) Emil : nnhievers@yhoo.o.in, mkhry_ops@yhoo.om 1 C:\AJES\AJES 21(2)\Finl\17. Ann revise 17.4.p65

2 Chursi, A et l. (2007) Asin J. Exp. Si., 21(2), n ironitione room t 24º. The nimls were trete with 100 mg/kg of lloxn monohyrte in norml sline. The rts whih showe loo gluose level more thn 140 mg% 20 ys fter injetion of lloxn were inlue in the stuy. Animl were ivie into following group, eh group hve 6 nimls. Group A - Norml Control Group B - Dieti Control Group C - Rosiglitzone Control Group D - Rosiglitzone (2mg/kg) + Rifmpiin (10 mg/kg) Group E - Rosiglitzone (2mg/kg) + Phenoritone (20mg/kg) Group F - Rosiglitzone (2mg/kg) + Phenytoin (25 mg/kg) All the ove enzyme inuers suh s phenytoin, phenoritone n rifmpiin (Atls E. n Turk, M.1968; Young et. l., 2004) were mixe with rosiglitzone powere rug n given orlly y gstri tue, smple of loo ws withrwn y retro-oritl punture just prior to ministrtion of rug n lso t perioil intervls upto three hours. The loo gluose level, retinine level n H.D.L. holesterol level hve een etermine y Autonlyzer (Allin et. l., 1974). Result n Disussion : Aoring to grphil representtion (Fig. 1 n 2) n tulte vlue's (Tle 1 n 2) it hs een epite tht rosiglitizone - stnr ntiieti rug when given orlly to ieti rt's, 20 ys fter prouing ietis y lloxn, showe erese loo gluose level from 17% to 45% within the perio of 2.5 hrs. Rifmpiin, Phenoritone n Phenytion the ommon enzyme inuer's when given with rosiglitzone seprtely to the sme ieti rt's, the effet of rosiglitzone ws foun to e reue (Young et. l., 2004; Peru, 1982; Rj Kpoor n Kvimni, 2004). Bloo gluose level ws reue from 17% to 8%, 7%, 8% n 45% to 36%, 35%, 33% from perio of 2.5 hrs. When rifmipiin, phenoritone, phenytoin were give to rt's long with rosiglitzone respetively. Result shown tht rosiglitzone rug omine with enzyme inuers suh s rifmpiin, phenoritone n phenytoin lowere the therpeuti effiy of rosiglitzone. Beuse enzyme inuer's inue ytohrome P450 y enhning the rte of its synthesis n/or reuing the rte of egrtion (Bl D. K.n Dnhih A. P., 2001). Therefore omine ministrtion of enzyme inuers with rosiglitzone is not visle. Sine the hypoglyemi effet of the rug is reue (Young et. l., 2004). Summry n Conlusion : The effet of enzyme inuer's in therpeuti effiy of rosiglitzone, shown tht rosilitzone inue the hypoglyemi y inreses skeletl musles ells sensitivity to insulin n erese hepti gluose proution. Sine omine ministrtion of rosiglitzone with three ifferent enzyme inuer's lter the therpeuti effiy of rosiglitzone ue to inution of ytohrome P450 mirosoml enzyme y enhning the rte of its egrtion. Therefore its onlue tht omine ministrtion of enzyme inuer's - rifmpiin, phenoritone, phenytoin with rosiglitzone shoul e voie. 2 C:\AJES\AJES 21(2)\Finl\17. Ann revise 17.4.p65

3 Effets of Enzyme Inuers in Therpeuti Effiy of Rosiglitzone Tle 1 : The Effet of Enzyme Inuers on Bloo Gluose Level Gr. No Tretment Plsm sugr level (mg/l) 2.0 hr 2.5 hr 3.0 hr Initil 0.5 hr 1.0 hr 1.5 hr A Norml ontrol B Dieti ontrol (lloxn 100mg/kg i.p) C Rosiglitzone ontrol (2 mg/kg p.o) D Rosiglitzone + Rifmpiin (2 mg/kg p.o) (10 mg/kg p.o) E Rosiglitzone + Phenoritone (2 mg/kg p.o) (20 mg/kg p.o) F Rosiglitzone + Phenytoin (2 mg/kg p.o) (25 mg/kg p.o) 67.20± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.6 0 Eh vlue is the men of 6 rt's ±S.E ==> p < 0.05 ==> p < 0.02 ==> p < 0.01 ==> p< ==> Non- signifint 3 C:\AJES\AJES 21(2)\Finl\17. Ann revise 17.4.p65

4 Chursi, A et l. (2007) Asin J. Exp. Si., 21(2), Tle 2 : Totl Bloo Cholesterol, Hl Cholesterol An Cretinine Level ( mg/l) Tretment PARAMETER S Plsm totl holesterol Plsm HDL holesterol Initil After 3 hrs Initil After 3 hrs Initil Plsm retinine After 3 hrs ontrol 81.24± ± ± ± ± ±0.01 ontrol (lloxn kg i.p) 87.25± ± ± ± ± ±0.01 zone ontrol g p.o) 85.57±0.30 zone + Rifmpiin kg p.o) (10 mg/kg p.o) 84.80±0.46 zone + Phenoritone g p.o) (20 mg/kg p.o) 86.73±0.39 zone + Phenytoin g p.o) (25 mg/kg p.o) 86.70± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.03 Eh vlue is the men of 6 rt's ±S.E ==> p < 0.05 ==> p < 0.02 ==> p < 0.01 ==> p< ==> Non- signifint 4 C:\AJES\AJES 21(2)\Finl\17. Ann revise 17.4.p65

5 Effets of Enzyme Inuers in Therpeuti Effiy of Rosiglitzone Fig. 1 : The effet of rosiglitzone with ezyme inuers on hyperglyemi rts Norm l ontrol Dietiontrol Rosiglitzone ontrol Ros iglitzone + Rifm piin Rosiglitzone + Phenoritone Rosiglitzone + Phenytoion 160 Bloo sugr level in mg/l Tim e in Hours Fig. 2 : The effet of rosiglitzone with ezyme inuers on hyperglyemi rts Norm l ontrol Dietiontrol Rosiglitzone ontrol Rosiglitzone + Rifm piin Rosiglitzone + Phenoritone Rosiglitzone + Phenytoion Bloo sugr level in mg/l Time in Hours 5 C:\AJES\AJES 21(2)\Finl\17. Ann revise 17.4.p65

6 Chursi, A et l. (2007) Asin J. Exp. Si., 21(2), Referenes : Allin C. C., Poon L. S. n Chn, C. S. (1974): Enzymti etermintion of totl serum holesterol. Clinil Chemistry. 20, Atls E. n Turk, M. (1968): Lortory n linil investigtion of Rifmpiin. Amerin Journl of the Meil Siene. 256, Bl D. K. n Dnhih A. P., (2001): Cytohrome P450 n rug intertions. Inin Journl of Phrmology. 33 : Ji-Young., Kyoung-Ah Kim., Mun-Ho Kng. n Su-Lyun Kim BS. n Je-Gook Shin (2004): Effet of Rifmpiin on the phrmokineti of Rosiglitzole in helthy sujet. Clinil Phrmology & Therpeuti. 75(3), Peru E. (1982): Phrmokineti intertions with nti-epilepti rugs. Clinil Phrmokineti. 7, Rj Kpoor B.n Kvimni S. (2004): Effet of enzyme inuers on therpeuti effiy of merin psule. The Anitsepti. 98, C:\AJES\AJES 21(2)\Finl\17. Ann revise 17.4.p65