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 Later after 18h fast they were again given the combined treatment on the seventh day and blood samples were withdrawn.COLLECTION OF BLOOD SAMPLES:blood samples were collected from the marginal ear vein of rabbits at 0, 1, 2, 3, 4, 6, 8, 12, 18 and 24 hours after drug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.

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• 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.