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Transcript of pharmacokinetic and pharmacodynamic interactions between Atorvastatin and Glimipiride in normal...
Pharmacokinetic and Pharmacodynamic
Interactions between Atorvastatin and
Glimpiride in normal Rabbits
GuideDr. N. AnithaM.Pharm, PhDAsst.ProfessorDept of PharmacologySUCP
Author
Soobiya Majeed
M, Pharmacy 1st yr
Sultan- ul- Uloom College
of Pharmacy
CONTENTS
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
CONCLUSION
BIBLIOGRAPHY
Introduction
• Atorvastatin - trade name Lipitor
• Antihyperlipidimic drug.
• Mechanism of action
• Glimepiride is a second generation sulfonylurea, antidiabetic drug.
• Mechanism of action
Materials and methods
Albino rabbit -Wt. 1.5 and 1.7 kgFasted – 18hGlimepirideGlibenclamideAtorvastatinAcetonitrileHCl 1NGlucose kit
Administration of drug
Oral administration with a stomach tube.5ml of distilled waterReq quantity of drug0.5 ml of distilled water
Experimental methods• SINGLE DOSE TREATMENT WITH SELECTED DRUG:• The rabbits were divided into the following groups of five
animals in each and experiment was conducted as per the following stages.
• Stage I: Three groups of rabbits were administered with 0.28, 0.56 and 1.12mg/kg body weight of glimepiride respectively to obtain the dose effective relationship of glimepiride.
• Stage II: Rabbits in this group were treated with half therapeutic dose (1/2 TD, 0.28mg/1.5kg body weight) of glimepiride and blood samples were collected at regular intervals and analyzed for blood glucose and serum glimepiride levels.
• Stage III: After a wash out period of seven days, the same rabbits(Stage II) of animals were treated with interacting drug atorvastatin (0.7mg/1.5kg body weight).
• Stage IV: After a wash out period of seven days, the animals were treated with a combination of atorvastatin (0.7mg/1.5kg body weight) followed by glimepiride (0.28mg/1.5kg body weight) after 30 minutes.
MULTIPLE DOSE TREATMENT WITH THE SELECTED DRUG: After interaction study in stage IV, the two groups of rabbits were continued with the daily treatment of interacting drugs for the next six days with regular feeding. Later after 18h fast they were again given the combined treatment on the seventh day and blood samples were withdrawn.COLLECTION OF BLOOD SAMPLES:blood samples were collected from the marginal ear vein of rabbits at 0, 1, 2, 3, 4, 6, 8, 12, 18 and 24 hours after drug treatment.
Concentration
added
(ng/mL)
Concentration
found
(ng/mL)
Standard
Deviation
Coefficient of
variation
(%)
10 9.346 1.052 10.274
20 18.306 0.451 8.469
50 45.440 0.465 9.118
100 101.169 1.710 1.697
200 206.815 3.066 3.407
400 386.592 2.455 3.349
800 840.886 12.864 5.108
1000 971.441 9.447 2.852
Table 1: Intra-day variability of the assay for glimepiride in serum
(n=3)
Concentration
added
(ng/mL)
Concentration
found
(ng/mL)
Standard
Deviation
Coefficient of
variation
(%)
10 10.021 1.452 12.571
20 20.122 2.199 9.523
50 48.838 3.913 6.327
100 103.446 3.185 3.447
200 206.351 3.047 3.176
400 377.087 8.859 5.728
800 832.626 17.046 4.077
1000 981.504 15.718 1.849
Table 2: Inter-day variability of the assay for glimepiride in serum (n=4).
Kinetic Parameters RB1 RB2 RB3 RB4 RB5 Mean ± SEM
AUC24h (ng*h/mL) 2439.586 2871.275 2803.242 3046.546 3193.738 2870.878± 127.6
AUCinf(ng*h/mL) 2759.676 3422.549 3275.47 4015.723 3538.418 3402.367± 203.0
AUMC24h(ng*h*h/mL) 24346.40 30081.16 28362.49 31373.26 32356.02 29303.87± 1408.3
AUMCinf(ng*h*h/mL) 35074.94 49329.61 44651.51 68946.44 43598.46 48320.19± 5646.5
Kel (h-1) 0.081949 0.063425 0.072824 0.059902 0.080041 0.071628 ± 0.0
Ka (h-1) 0.586 0.725 0.684 0.748 0.618 0.6722 ± 0.0
T1/2 (h) 6.60 7.57 7.27 10.23 5.97 7.527739 ± 0.7
MRT(h) 12.71 14.41 13.63 17.17 12.32 14.04912 ± 0.9
Vdarea(mL) 1545.02 1339.60 1525.01 1647.55 1159.19 1443.274 ±86.7
Vd area (mL/kg) 965.63 893.07 897.06 1029.72 681.88 893.4729 ±58.5
Tmax (h) 3 3 3 3 3 3 ± 0.0
Cmax (ng/mL) 199.38 192.65 210.06 223.41 216.21 208.34 ± 5.6
Table 3: Pharmacokinetics parameters of acute administration of glimepiride in
Normal Rabbits. (n=5)
RB1 RB2 RB3 RB4 RB5 Mean ± SEM
AUC24h
(ng*h/mL)
2846.966 3043.604 3266.886 3247.575 3736.686 3228.344 ± 148.3
AUCinf(ng*h/
mL)
3171.404 3984.916 4141.524 4551.074 4941.468 4158.077 ± 297.7
AUMC24h(ng
*h*h/mL)
28001.63 31029.31 33029.23 32615.14 38815.00 32698.06 ± 1766.0
AUMCinf(ng*
h*h/mL)
38671.97 67127.42 65690.21 87335.12 85594.93 68883.93 ± 8791.3
Kel (h-1) 0.086936 0.062613 0.067409 0.064095 0.058615 0.067934 ± 0
Ka (h-1) 0.536 0.699 0.613 0.503 0.627 0.5956 ± 0
T1/2 (h) 6.16 9.94 9.25 12.46 10.28 9.617116 ± 1.0
MRT(h) 12.19 16.85 15.86 19.19 17.32 16.28249 ± 1.2
Vd area
(mL)
1255.64 1512.32 1533.48 1769.85 1428.40 1499.937 ± 83.3
Vd area
(mL/kg)
784.77 1008.21 902.05 1106.16 840.23 928.2848 ± 57.9
Tmax (h) 3 3 3 3 3 3 ± 0
Cmax
(ng/mL)
240.16 242.47 268.81 280.53 278.49 262.092 ± 8.7
Table 4: Pharmacokinetic parameters of acute administration of atorvastatin in
normal rabbits (n=5).
**Significant at P<0.01, *Significant at P<0.05 compared to glimepiride control.
Fig 6: The percent Blood glucose change with different doses of glimepiride in normal rabbits (n=5
Fig 7: Effect of Acute administration of atorvastatin on
the Hypoglycemic activity of glimepiride in normal
rabbits (n=5).
Fig 8: Effect of Chronic administration of
atorvastatin on the Hypoglycemic activity of
glimepiride in normal rabbits (n=5).
Fig 9: Serum Glimepiride concentration VS time in
normal rabbits treated with atorvastatin (N=5).
Discussion• Glimepiride produced dose dependent decrease in blood
glucose levels with 1 /2TD , 1TD and 2 TD doses.
• Glimepiride produced hypoglycemic effect with peak effect at 3hours in rabbits.
• In rabbits atorvastatin had minor effect on blood glucose levels,but it enhanced the hypoglycemic effect of glimepiride whenadministered in combination.
• There was significant rise in pharmacokinetic parameters likeAUC, AUMC and Cmax of glimepiride with single dose treatmentof atorvastatin. The increase in AUC and AUMC indicatesimproved availability of glimepiride in presence of atorvastatin.
• The increased bioavailability cannot be due to improvedabsorption, since absorption rate and absorption half-life ofglimepiride were not altered.
• The drug profile of Glimepiride shows that it is a highly bounddrug i.e, about 99.5% was bound to plasma proteins.
• Atorvastatin is also highly bound to the protein up to 98%.• Since glimepiride and atorvastatin are highly protein bound
drugs they may compete with each other for the same proteinbinding site.
• Atorvastatin is known to be metabolized to a major extent byCYP4503A4 and to a minor extent by CYP4502C9.
• Glimepiride is mainly metabolized by CYP4502C9.• Atorvastatin inhibits the enzyme CYP4502C9 and delay the
metabolism of glimepiride.• Hence the enhancement of glimepiride response in the presence
of atorvastatin might be because of pharmacokinetic mechanismsnamely inhibition of its metabolism coupled with displacementfrom protein binding sites.
Conclusion• Atorvastatin produced minor hypoglycemic effect in
normal rabbits when administered alone, but enhanced the hypoglycemic effect of glimepiride when coadministered.
• AUC, AUMC and Cmax of glimepiride were increased in presence of atorvastatin indicating improved systemic availability of glimepiride.
• There was no significant change in Ka and Kel of Glimepiride.
• The interaction produced appears to be Pharmacokinetic mechanisms mainly inhibition of its metabolism coupled with displacement from protein binding sites.
•
Bibliography• Lins RL, Matthys KE, Verpooten GA, Peeters PC, Dratawa M, Stolear
JC et al. Pharmacokinetics of atorvastatin and metabolites aftersingle and multiple dosing in hypercholesterolemic haemodialysispatients. Neph Dia. Transplant. 2003;18(5)967-976.
• White CM and Chow MS. A review of HMG-CoA reductaseinhibitors. U.S Pharm. 1998; HS19-HS30.208.Desager JP andHormans Y. Clinical pharmacokinetics of 3-hydroxy- 3-hydroxymethylglutary-coenzyme A. reductase inhibitors. ClinPharmacokinet. 1996; 31: 348-371.
• Lennernas H and Fager G. Pharmacodynamics andpharmacokinetics of the HMG-CoA reductase inhibitors. ClinPharmacokinet. 1997; 32: 403-425.
• Rosenkranz B, Profozic V, Metelko Z, Mrzljak V, Lange C andMalerczyk V. Pharmacokinetics and safety of glimepiride at clinicallyeffective doses in diabetic patients with renal impairment.Diabetologia. 1996; 39: 1617-1624.