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Drug Metabolism and Pharmacokinetics Core

Drug Metabolism and Pharmacokinetics Core. Goal: To provide comprehensive pharmacology support for preclinical and clinical research. Services:. Pharmacokinetic studies: Quantify drug levels in serum/plasma, tissue or cells

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Drug Metabolism and Pharmacokinetics Core

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  1. Drug Metabolism and Pharmacokinetics Core Goal: To provide comprehensive pharmacology support for preclinical and clinical research

  2. Services: • Pharmacokinetic studies: Quantify drug levels in serum/plasma, tissue or cells • Evaluation of Organ Toxicity: Blood chemistry analysis for liver, kidney and bone marrow toxicity • Hematology: Measure complete blood counts • Measure GSH/GSSG • Redox analysis: Detection of protein thiol status in cells, tissue, serum and plasma. • Education and training

  3. NOV-002, a myeloproliferative agent Phase II: Neo-adjuvant breast cancer trial at MUSC

  4. Pharmacokinetic Analysis

  5. A. ug/mL GSSG B. ug/mL GSH

  6. Estimated pharmacokinetic parameters for NOV-002 (GSSG) and its primary metabolite (GSH) PK ParameterGSH GSSG Co (ug/mL) 4.10 0.65 Cmax (ug/mL) 18.30 2.16 Tmax (hr) 0.16 0.15 Volume of distribution, V/F (L/kg) 42.61 K01 (absorption rate constant), hr-1 6.42 K10 (elimination rate constant), hr-15.81 6.40 AUC 0-30min (ug.h/mL)6.37 1.18 Clearance, CL/F (L/hr/kg) 273.15

  7. Evaluation of Organ Toxicity

  8. Table 2. Mortality and Nephrotoxicity of Cisplatin in Mice • Elevated Abnormal • Mortality Creatinine Renal Histology • Saline 0/6* 0/6 0/6 • NOV-002 0/6 0/6 0/6 • Cisplatin 1/8§ 6/7§ 7/7§ • Cisplatin + NOV-002 0/9 3/9 3/9 • Data are the number of mice who died, had elevated plasma creatinine (>0.2 mg/dL) or abnormal renal histology over the number of mice treated. • § Statistically significant differences between treatment groups were detected with a Fisher Exact Test, P<0.01.

  9. Saline NOV-002 Cisplatin Cisplatin + NOV-002

  10. Hematology:

  11. Normal 6 x 109 Female +/+ x 109 cells/mL Female Male Cisplatin + + NOV-002 - + Cisplatin Induced Bone Marrow ToxicityWhite Blood Cells • HM2 Hematology System (Abaxis)

  12. Measure GSH/GSSGRedox Potential Eh (mV)

  13. -S-TGTM + TGTM -SH -S-SG + NOV-002 Redox analysis: * * % Free Sulfhydryls * *

  14. NOV-002 (25 mg/kg, iv) 0 ¼ ½ 1 4 24 h Kda 150 100 75 50 37 A B C D WB: PSSG WB: actin Identification of Plasma Markers following NOV-002 treatment

  15. Cost Recovery System: • Assay Development $1,500 + Column • PK Modeling $50/ hr • Plasma / Serum Assay $50 / sample • Organ toxicity analysis $35 / sample • Hematology (CBC) $20 / sample • GSH/GSSG levels $25 / sample • Protein Thiol Analysis $35 / sample • Breeze HPLC • User Operated Training $ 50 / hour • User Operation fee $ 25 / hour • Over-night / weekend fee $18 / hour

  16. Drug Metabolism and Pharmacokinetics Core Drug Discovery Building 420 843-876-2391 Danyelle Townsend, Ph.D., Director Yefim Manevich, Ph.D., Drug Discovery Building 420 manevich@musc.edu 843-876-2391 townsed@musc.edu Joachim Uys, Ph.D. PK project manager uys@musc.edu

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