Reference SummaryTannehill-Gregg SH, Toxicol Sci 2007 Jul;98(1):258-70

Title

 Rodent carcinogenicity profile of the antidiabetic dual PPAR alpha and gamma agonist muraglitazar.

Authors

 Tannehill-Gregg SH; Sanderson TP; Minnema D; Voelker R; Ulland B; Cohen SM; Arnold LL; Schilling BE; Waites CR; Dominick MA

Journal

 Toxicol Sci

Volume

 98

Issue

 1

Year

 2007

Pages

 258-70

Abstract

 The carcinogenic potential of muraglitazar, a dual human peroxisome proliferator-activated receptor alpha/gamma agonist, was evaluated in 2-year studies in mice (1, 5, 20, and 40 mg/kg) and rats (1, 5, 30, and 50 mg/kg). Benign gallbladder adenomas occurred at low incidences in male mice at 20 and 40 mg/kg (area under the curve [AUC] exposures > or = 62 times human exposure at 5 mg/day) and were considered drug related due to an increased incidence of gallbladder mucosal hyperplasia at these doses. There was a dose-related increased incidence of transitional cell papilloma and carcinoma of the urinary bladder in male rats at 5, 30, and 50 mg/kg (AUC exposures > or = 8 times human exposure at 5 mg/day). At 30 and 50 mg/kg, the urinary bladder tumors were accompanied by evidence of increased urine solids. Subsequent investigative studies established that the urinary bladder carcinogenic effect was mediated by urolithiasis rather than a direct pharmacologic effect on urothelium. Incidences of subcutaneous liposarcoma in male rats and subcutaneous lipoma in female rats were increased at 50 mg/kg (AUC exposures > or = 48 times human exposure at 5 mg/day) and attributed, in part, to persistent pharmacologic stimulation of preadipocytes. Toxicologically relevant nonneoplastic changes in target tissues included thinning of cortical bone in mice and hyperplastic and metaplastic adipocyte changes in mice and rats. Considering that muraglitazar is nongenotoxic, the observed tumorigenic effects in mice and rats have no established clinical relevance since they occurred at either clinically nonrelevant exposures (gallbladder and adipose tumors) or by a species-specific mechanism (urinary bladder tumors).

Links

 J:138038 – MGI References
17426106 – National Library of Medicine/PubMed

Strain Notes

Strain Note
CD-1 These mice were purchased from Charles River Laboratories, Raleigh, NC.

Models
Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
CD-1 Adrenal gland - Cortex adenoma Adrenal gland - Cortex

0 - 1.7
CD-1 Adrenal gland - Cortex adenoma
  • muraglitazar
 Adrenal gland - Cortex

0
CD-1 Adrenal gland - Medulla pheochromocytoma Adrenal gland - Medulla

0 - 1.7
CD-1 Adrenal gland - Medulla pheochromocytoma
  • muraglitazar
 Adrenal gland - Medulla

0
CD-1 Adrenal gland - Medulla pheochromocytoma - malignant Adrenal gland - Medulla

0 - 1.7
CD-1 Adrenal gland - Medulla pheochromocytoma - malignant
  • muraglitazar
 Adrenal gland - Medulla

0 - 1.7
CD-1 Adrenal gland - Subcapsular cell adenoma Adrenal gland - Subcapsular cell

0 - 1.7
CD-1 Adrenal gland - Subcapsular cell adenoma
  • muraglitazar
 Adrenal gland - Subcapsular cell

0 - 1.7
CD-1 Blood vessel hemangioma Blood vessel

0 - 3.3
CD-1 Blood vessel hemangioma
  • muraglitazar
 Blood vessel

0 - 3.3
CD-1 Blood vessel hemangioma Spleen

1.7
CD-1 Blood vessel hemangioma Uterus

1.7
CD-1 Blood vessel hemangiosarcoma Blood vessel

0 - 6.7
CD-1 Blood vessel hemangiosarcoma Spleen

1.7 - 5.0
CD-1 Blood vessel hemangiosarcoma Liver

1.7 - 5.0
CD-1 Blood vessel hemangiosarcoma Testis

1.7
CD-1 Blood vessel hemangiosarcoma Bone marrow

1.7
CD-1 Blood vessel hemangiosarcoma Subcutis

20 - 50
CD-1 Blood vessel hemangiosarcoma Gallbladder

2.5
CD-1 Blood vessel hemangiosarcoma
  • muraglitazar
 Blood vessel

1.7 - 8.3
CD-1 Blood vessel hemangiosarcoma
  • muraglitazar
 Spleen

1.7 - 6.7
CD-1 Blood vessel hemangiosarcoma
  • muraglitazar
 Liver

3.3 - 6.7
CD-1 Blood vessel hemangiosarcoma
  • muraglitazar
 Subcutis

14 - 100
CD-1 Blood vessel tumor Blood vessel

3.3 - 6.7
CD-1 Blood vessel tumor
  • muraglitazar
 Blood vessel

1.7 - 8.3
CD-1 Blood vessel tumor Lung

1.7
CD-1 Blood vessel tumor Uterus

1.7
CD-1 Blood vessel tumor Spleen

1.7
CD-1 Blood vessel tumor Liver

1.7
CD-1 Blood vessel tumor
  • muraglitazar
 Liver

1.7 - 8.3
CD-1 Blood vessel tumor
  • muraglitazar
 Ovary

1.7 - 3.3
CD-1 Blood vessel tumor
  • muraglitazar
 Uterus

3.3
CD-1 Blood vessel tumor
  • muraglitazar
 Spleen

1.7 - 3.3
CD-1 Blood vessel tumor
  • muraglitazar
 Bone marrow

1.7
CD-1 Blood vessel tumor
  • muraglitazar
 Subcutis

1.7 - 33
CD-1 Blood vessel tumor
  • muraglitazar
 Lung

1.7
CD-1 Bone osteosarcoma Subcutis

0
CD-1 Bone osteosarcoma
  • muraglitazar
 Subcutis

0 - 5.9
CD-1 Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

very low
CD-1 Connective tissue - Fibroblast fibrosarcoma Subcutis

0 - 75
CD-1 Connective tissue - Fibroblast fibrosarcoma Abdominal cavity

0 - 50
CD-1 Connective tissue - Fibroblast fibrosarcoma
  • muraglitazar
 Subcutis

0 - 100
CD-1 Connective tissue - Fibroblast fibrosarcoma
  • muraglitazar
 Abdominal cavity

0
CD-1 Eye - Harderian gland adenoma Eye - Harderian gland

3.3 - 13
CD-1 Eye - Harderian gland adenoma
  • muraglitazar
 Eye - Harderian gland

0 - 6.8
CD-1 Eye - Harderian gland carcinoma Eye - Harderian gland

0 - 3.3
CD-1 Eye - Harderian gland carcinoma
  • muraglitazar
 Eye - Harderian gland

0 - 1.7
CD-1 Forestomach squamous cell carcinoma Forestomach

0
CD-1 Forestomach squamous cell carcinoma
  • muraglitazar
 Forestomach

0 - 1.7
CD-1 Forestomach squamous cell papilloma Forestomach

0 - 1.7
CD-1 Forestomach squamous cell papilloma
  • muraglitazar
 Forestomach

0
CD-1 Gallbladder adenoma Gallbladder

0
CD-1 Gallbladder adenoma
  • muraglitazar
 Gallbladder

0 - 3.3
CD-1 Gallbladder hyperplasia - focal Gallbladder

0 - observed
CD-1 Gallbladder hyperplasia - focal
  • muraglitazar
 Gallbladder

0 - observed
CD-1 Head squamous cell carcinoma
  • muraglitazar
 Head

50
CD-1 Head squamous cell carcinoma Head

0
CD-1 Head squamous cell papilloma
  • muraglitazar
 Head

0
CD-1 Head squamous cell papilloma Head

100
CD-1 Intestine - Small Intestine - Duodenum adenoma Intestine - Small Intestine - Duodenum

0
CD-1 Intestine - Small Intestine - Duodenum adenoma
  • muraglitazar
 Intestine - Small Intestine - Duodenum

0 - 1.7
CD-1 Intestine - Small Intestine - Jejunum carcinoma Intestine - Small Intestine - Jejunum

0
CD-1 Intestine - Small Intestine - Jejunum carcinoma
  • muraglitazar
 Intestine - Small Intestine - Jejunum

0 - 1.7
CD-1 Kidney adenoma - tubular Kidney

0
CD-1 Kidney adenoma - tubular
  • muraglitazar
 Kidney

0 - 1.7
CD-1 Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma Leukocyte - Monocyte - Macrophage - Histiocyte

0 - 15
CD-1 Leukocyte - Monocyte - Macrophage - Histiocyte histiocytic sarcoma
  • muraglitazar
 Leukocyte - Monocyte - Macrophage - Histiocyte

0 - 10
CD-1 Leukocyte - Myelocyte (Granulocyte) - Basophil - Mast cell leukemia Leukocyte - Myelocyte (Granulocyte) - Basophil - Mast cell

0 - 1.7
CD-1 Leukocyte - Myelocyte (Granulocyte) - Basophil - Mast cell leukemia
  • muraglitazar
 Leukocyte - Myelocyte (Granulocyte) - Basophil - Mast cell

0
CD-1 Leukocyte - Myelocyte (Granulocyte) leukemia - myelocytic Leukocyte - Myelocyte (Granulocyte)

0 - 1.7
CD-1 Leukocyte - Myelocyte (Granulocyte) leukemia - myelocytic
  • muraglitazar
 Leukocyte - Myelocyte (Granulocyte)

0
CD-1 Leukocyte lymphoma Leukocyte

1.7 - 18
CD-1 Leukocyte lymphoma
  • muraglitazar
 Leukocyte

3.3 - 22
CD-1 Leukocyte neoplasm Leukocyte

observed - 6.7
CD-1 Leukocyte neoplasm
  • muraglitazar
 Leukocyte

observed - 10
CD-1 Liver hepatocellular adenoma Liver

0 - 8.3
CD-1 Liver hepatocellular adenoma
  • muraglitazar
 Liver

0 - 5.0
CD-1 Liver hepatocellular carcinoma Liver

0 - 3.3
CD-1 Liver hepatocellular carcinoma
  • muraglitazar
 Liver

0 - 6.7
CD-1 Lung adenoma Lung

5.0 - 13
CD-1 Lung adenoma
  • muraglitazar
 Lung

5.0 - 15
CD-1 Lung carcinoma Lung

5.0 - 10
CD-1 Lung carcinoma
  • muraglitazar
 Lung

1.7 - 13
CD-1 Lung tumor Lung

13 - 20
CD-1 Lung tumor
  • muraglitazar
 Lung

6.7 - 27
CD-1 Mammary gland carcinoma Mammary gland

0 - 2.0
CD-1 Mammary gland carcinoma
  • muraglitazar
 Mammary gland

0 - 6.8
CD-1 Mesodermal cell/mesoblast myxosarcoma Subcutis

0
CD-1 Mesodermal cell/mesoblast myxosarcoma
  • muraglitazar
 Subcutis

0 - 50
CD-1 Mesodermal cell/mesoblast myxosarcoma Abdominal cavity

0 - 17
CD-1 Mesodermal cell/mesoblast myxosarcoma
  • muraglitazar
 Abdominal cavity

0
CD-1 Mesodermal cell/mesoblast sarcoma CNS - Meninges

0
CD-1 Mesodermal cell/mesoblast sarcoma
  • muraglitazar
 CNS - Meninges

0 - 1.7
CD-1 Mesodermal cell/mesoblast sarcoma - stromal Uterus - Endometrium - Stroma

0
CD-1 Mesodermal cell/mesoblast sarcoma - stromal Uterus - Cervix - Stroma

0
CD-1 Mesodermal cell/mesoblast sarcoma - stromal
  • muraglitazar
 Uterus - Endometrium - Stroma

0 - 1.7
CD-1 Mesodermal cell/mesoblast sarcoma - stromal
  • muraglitazar
 Uterus - Cervix - Stroma

0 - 1.8
CD-1 Mesothelium mesothelioma Thoracic cavity

0
CD-1 Mesothelium mesothelioma
  • muraglitazar
 Thoracic cavity

0 - 12.5
CD-1 Muscle - Smooth leiomyoma Uterus

0 - 1.7
CD-1 Muscle - Smooth leiomyoma Uterus - Cervix

0 - 1.7
CD-1 Muscle - Smooth leiomyoma
  • muraglitazar
 Uterus

0 - 1.7
CD-1 Muscle - Smooth leiomyoma
  • muraglitazar
 Uterus - Cervix

0 - 3.6
CD-1 Muscle - Smooth leiomyoma Urinary bladder

0 - 1.7
CD-1 Muscle - Smooth leiomyoma
  • muraglitazar
 Urinary bladder

0
CD-1 Muscle - Smooth leiomyosarcoma Uterus

0 - 1.7
CD-1 Muscle - Smooth leiomyosarcoma
  • muraglitazar
 Uterus

0 - 1.7
CD-1 Ovary adenoma Ovary

3.3 - 3.4
CD-1 Ovary adenoma
  • muraglitazar
 Ovary

1.7 - 6.7
CD-1 Ovary adenoma - tubulostromal Ovary

0 - 1.7
CD-1 Ovary adenoma - tubulostromal
  • muraglitazar
 Ovary

0
CD-1 Ovary cystadenoma Ovary

5.0
CD-1 Ovary cystadenoma
  • muraglitazar
 Ovary

0
CD-1 Ovary luteoma Ovary

0 - 1.7
CD-1 Ovary luteoma
  • muraglitazar
 Ovary

0
CD-1 Ovary tumor - granulosa-theca cell - benign Ovary

3.3
CD-1 Ovary tumor - granulosa-theca cell - benign
  • muraglitazar
 Ovary

0
CD-1 Ovary tumor - granulosa-theca cell - malignant Ovary

3.3
CD-1 Ovary tumor - granulosa-theca cell - malignant
  • muraglitazar
 Ovary

0
CD-1 PNS - Schwann cell neurofibrosarcoma Skin

0
CD-1 PNS - Schwann cell neurofibrosarcoma
  • muraglitazar
 Skin

0 - 8.3
CD-1 Parathyroid gland adenoma Parathyroid gland

0
CD-1 Parathyroid gland adenoma
  • muraglitazar
 Parathyroid gland

0 - 2.4
CD-1 Pituitary gland adenoma Pituitary gland

0 - 5.1
CD-1 Pituitary gland adenoma
  • muraglitazar
 Pituitary gland

0 - 5.1
CD-1 Skin squamous cell papilloma Skin

0 - 20
CD-1 Skin squamous cell papilloma
  • muraglitazar
 Skin

0
CD-1 Stomach - Glandular carcinoma Stomach - Glandular

0 - 1.7
CD-1 Stomach - Glandular carcinoma
  • muraglitazar
 Stomach - Glandular

0
CD-1 Testis - Leydig cell (Interstitial cell) tumor - benign Testis - Leydig cell (Interstitial cell)

0 - 1.7
CD-1 Testis - Leydig cell (Interstitial cell) tumor - benign
  • muraglitazar
 Testis - Leydig cell (Interstitial cell)

0 - 3.3
CD-1 Testis - Rete testis adenoma Testis - Rete testis

0 - 1.7
CD-1 Testis - Rete testis adenoma
  • muraglitazar
 Testis - Rete testis

0
CD-1 Thyroid gland - Follicular cell adenoma Thyroid gland - Follicular cell

0 - 3.3
CD-1 Thyroid gland - Follicular cell adenoma
  • muraglitazar
 Thyroid gland - Follicular cell

0 - 1.7
CD-1 Tooth ameloblastoma Tooth

100
CD-1 Uterus - Cervix - Stroma polyp Uterus - Cervix - Stroma

0
CD-1 Uterus - Cervix - Stroma polyp
  • muraglitazar
 Uterus - Cervix - Stroma

0 - 3.6
CD-1 Uterus - Cervix carcinoma Uterus - Cervix

0 - 1.7
CD-1 Uterus - Cervix carcinoma
  • muraglitazar
 Uterus - Cervix

0 - 1.8
CD-1 Uterus - Endometrium - Stroma polyp Uterus - Endometrium - Stroma

3.3 - 5.0
CD-1 Uterus - Endometrium - Stroma polyp
  • muraglitazar
 Uterus - Endometrium - Stroma

0 - 6.7
CD-1 Uterus adenoma Uterus

0
CD-1 Uterus adenoma
  • muraglitazar
 Uterus

0 - 1.7
CD-1 Uterus carcinoma Uterus

1.7
CD-1 Uterus carcinoma
  • muraglitazar
 Uterus

0 - 3.3