Drug Metabolism and Pharmacokinetics
Program Overview
The Drug Metabolism and Pharmacokinetics (DMPK) Core at CDI provides bioanalytical measurements for a wide array of chemotherapeutic agents to support basic research, lead compound optimization strategies and preclinical/clinical development.
DMPK Core’s Mission
The DMPK core at CDI provides small molecule drug and biologics quantification for many anti-infective drug discovery programs. Our methodologies have paved the way to measuring drug exposure in hard-to-reach sites of disease. By bridging local drug exposure measurements with potency readouts, our efforts are supporting the development of predictive PK-PD models and translational platforms.
Features/Capabilities
Our analysts are well-versed with diverse biological matrices that include, but are not limited to, plasma, tissue homogenates, urine, epithelial lining fluid (ELF), cerebrospinal fluid (CSF), cell culture medium and cell lysates. Analysts are also trained to process specimens containing infectious agents within biocontainment suites.
This DMPK core facility has the relevant personnel, equipment and experience to run PK studies in uninfected mice and rats. Comparative drug formulation, plasma PK, dose escalation and tolerability studies in rodents form our major contributions to multiple drug development consortia. By coupling rodent PK studies with our bioanalytical platform, we inform dosing strategies in preclinical efficacy studies and basic allometric scaling efforts.
The DMPK Core is also a member of the National Cancer Institute-designated Georgetown Lombardi Comprehensive Cancer Center (LCCC) Mass Spectrometry and Analytical Pharmacology Shared Resource (MSAPSR). The Lab welcomes collaborations with external scientists and will cater to individual experiment design, method development, results interpretation and manuscript preparation needs. Investigators interested in using this shared resource should contact Matthew Zimmerman to discuss scheduling and pricing.
Major bioanalytical services include
- Small molecule quantification in plasma & tissue
- Quantification of biologics in plasma & tissue
- Metabolite identification (MetID)
- Laser capture microdissection of specific tissue compartments
- Safe handling of biological specimens containing BSL-2 & BSL-3 pathogens
In vivo PK services include
- PO/IP/SC/IM dosing in mice/rats
- Full (24 h) PK studies with tissue collection
- Snapshot PK studies (limited time course)
- Dose escalation and tolerability studies
- Metabolic cage mass balance studies
- Application of CYP inhibitors to boost exposure
In vitro ADME services include
- Plasma and tissue protein binding assays
- Plasma and tissue stability assays
- Drug formulation screening and development
- Hepatic fraction (Microsomes, S9) stability assays
Major Instrumentation
AB Sciex 5500 QTRAP Mass Spectrometer coupled with ExionLC™ Series UHPLC System
The CDI houses 2 hybrid tandem quadrupole – linear ion trap mass spectrometers that are dedicated to LC-MS/MS analysis of drug compounds. These systems deliver high sensitivity and selectivity with reduced matrix interference for improved drug quantitation.
AB Sciex 6500+ QTRAP Mass Spectrometer coupled with Shimadzu Nexera X2 UHPLC system
This hybrid tandem quadrupole – linear ion trap mass spectrometer is predominantly used for ultra-sensitive LC-MS/MS quantification of drug compounds from challenging samples. This system enables the spatial quantitation of pharmaceuticals from cellular regions isolated using laser-capture microdissection.
AB Sciex 7500 QTRAP Mass Spectrometer coupled with Shimadzu 40AD UHPLC
The 7500 QTRAP has industry leading tandem quadrupole sensitivity. This mass spectrometer is used in applications requiring the highest levels of sensitivity. The 7500 QTRAP applied to drug quantification, metabolite identification, and targeted Omics (Metabolomics, Lipidomics).
Thermo Q-Exactive Quadrupole-Obitrap Mass Spectrometer coupled with UltiMate 3000 UHPLC
The hybrid system combines quadrupole precursor selection with high resolution accurate mass (HRAM). Orbitrap analysis and is predominantly used for the identification of unknown drug metabolites.
Leica Laser Microdissection Microscope 6
The LMD6 microscope is housed within one of CDIs BSL-3 laboratories and is dedicated to the dissection of regions of interest from infected tissue specimens for downstream antimicrobial drug quantitation.
Leica Laser Microdissection Microscope 7
The LMD7 microscope isolates specific cell populations from frozen/FFPE tissue sections and bone sections. The captured cells or regions of interest can then be post-processed for a wide range of downstream applications that includes small molecule and metabolite quantitation.
Key Staff/Faculty
Vidmantas Petraitis, MD
Director, DMPK Core
vidmantas.petraitis@hmh-cdi.org
Matthew Zimmerman
Manager, DMPK Core
Matthew.Zimmerman@HMH-CDI.org
Matt received his Chemical Engineering degree from the University of Kansas. Prior to joining CDI in 2019, he spent 5 years managing the DMPK facility at the Public Health Research Institute, Rutgers, and over 7 years as an analytical chemist at the Genomics Institute of the Novartis Research Foundation (GNF). He has published several peer reviewed articles (pubmed).
Firat Kaya
Supervisor, CDI Lab
Suyapa PenalvaLopez
Research Tech
Sindhuja Paruchuri
Research Tech
Julianna Cangialosi
Animal Technician Specialist
Camilla Folvar
Animal Technician Specialist
Selected publications from the DMPK core:
Sarathy JP, Zimmerman MD, Gengenbacher M, Dartois V, Dick T. Mycobacterium tuberculosis DprE1 Inhibitor OPC-167832 Is Active against Mycobacterium abscessus In Vitro. Antimicrob Agents Chemother. 2022 Dec 20;66(12):e0123722.
Kreutzfeldt KM, Jansen RS, Hartman TE, Gouzy A, Wang R, Krieger IV, Zimmerman MD, Gengenbacher M, Sarathy JP, Xie M, Dartois V, Sacchettini JC, Rhee KY, Schnappinger D, Ehrt S. CinA mediates multidrug tolerance in Mycobacterium tuberculosis. Nat Commun. 2022 Apr 22;13(1):2203.
Tasneen R, Garcia A, Converse PJ, Zimmerman MD, Dartois V, Kurbatova E, Vernon AA, Carr W, Stout JE, Dooley KE, Nuermberger EL. Novel Regimens of Bedaquiline-Pyrazinamide Combined with Moxifloxacin, Rifabutin, Delamanid and/or OPC-167832 in Murine Tuberculosis Models. Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0239821.
Kaya F, Ernest JP, LoMauro K, Gengenbacher M, Madani A, Aragaw WW, Zimmerman MD, Sarathy JP, Alvarez N, Daudelin I, Wang H, Lanni F, Weiner DM, Via LE, Barry CE 3rd, Olivier KN, Dick T, Podell BK, Savic RM, Dartois V. A Rabbit Model to Study Antibiotic Penetration at the Site of Infection for Nontuberculous Mycobacterial Lung Disease: Macrolide Case Study. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0221221.
Ernest JP, Sarathy J, Wang N, Kaya F, Zimmerman MD, Strydom N, Wang H, Xie M, Gengenbacher M, Via LE, Barry CE 3rd, Carter CL, Savic RM, Dartois V. Lesion Penetration and Activity Limit the Utility of Second-Line Injectable Agents in Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2021 Sep 17;65(10):e0050621.
Malwal SR, Zimmerman MD, Alvarez N, Sarathy JP, Dartois V, Nacy CA, Oldfield E. Structure, In Vivo Detection, and Antibacterial Activity of Metabolites of SQ109, an Anti-Infective Drug Candidate. ACS Infect Dis. 2021 Aug 13;7(8):2492-2507.