Neil R. Hartman
National Institutes of Health
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Clinical Pharmacology & Therapeutics | 1990
Neil R. Hartman; Robert Yarchoan; James M. Pluda; Rose V. Thomas; Kathy S. Marczyk; Samuel Broder; David G. Johns
This article describes the pharmacokinetics of 2′,3′‐dideoxyadenosine (ddA) and 2′,3′‐dideoxyinosine (ddI) as determined during phase I clinical trials in patients with acquired immunodeficiency syndrome and acquired immunodeficiency syndrome–related complex. Drug levels were determined by HPLC in plasma, cerebrospinal fluid, and urine after administration of the drugs either intravenously or as an oral liquid given with antacid. ddA was metabolized rapidly and quantitatively to ddI to such an extent that ddA was undetectable in the plasma even during continuous intravenous administration of ddA. The plasma kinetics of ddI were generally monoexponential and were characterized by a half‐life of 38 minutes. This probably does not accurately reflect the kinetics of the active species of ddI, which appears to be 2′,3′‐dideoxyadenosine triphosphate, formed intracellularly. Oral bioavailability was 38% for oral liquid given with antacid. The total body clearance averaged 1.00 L/kg/hr, with a volume of distribution of 1.01 L/kg. Approximately 36% of the intravenous dose could be recovered unchanged in the urine. The level of ddI in the cerebrospinal fluid 1 hour after drug infusion averaged 21% of that of the simultaneous plasma level. It is concluded that ddI has pharmacokinetic properties that are amenable to its clinical use.
Investigational New Drugs | 1991
Daniel S. Zaharko; James A. Kelley; Joseph E. Tomaszewski; Lajos Hegedus; Neil R. Hartman
SummaryA hybrid compartmental-physiological model for cyclopentenyl cytosine (CPE-C) is designed on the basis of early limited rodent pharmacokinetic data. Application of model independent pharmacokinetics and biochemical knowledge was first used to conceptualize such a model. The approach was to scale the physiological parameters of the model (compartmental clearances) and keep constant the anatomic parameters of the model (compartment volumes). Scaling of physiological mechanisms was based on body weight/surface area ratios. Using these principles, simulations with the model can reasonably anticipate the in vivo behavior of (CPE-C) in several species (mouse, rat, dog). The model is useful in understanding species differences in pharmacokinetic behavior of CPE-C.
Journal of Chromatography B: Biomedical Sciences and Applications | 1997
Lajos Hegedus; Harry Ford; Neil R. Hartman; James A. Kelley
Cyclopentenyl cytosine (CPE-C) is a synthetic carbocyclic nucleoside that possesses diverse antitumor and antiviral activity. CPE-C has been studied extensively at the preclinical level and has been evaluated in a Phase I clinical trial involving patients with solid tumors. A narrow-bore, reversed-phase HPLC method that has been developed for the sensitive measurement of CPE-C in plasma and urine in order to carry out these studies is described. Covalent solid-phase extraction based on an immobilized phenylboronic acid ligand is employed to isolate both CPE-C and endogenous ribonucleosides from the biological matrix selectively and efficiently. This is followed by isocratic elution of the extract with pH 5.0, 0.1 M ammonium formate buffer at 0.150 ml/min on a tandem, switchable, C18 narrow-bore (2.1 mm I.D.) column system in which the precolumn is automatically backflushed to eliminate late-eluting components. UV detection at 278 nm provides a limit of quantitation of 0.1 microM for CPE-C in rat and human plasma with a precision better than 4% for the range 1-20 microM in rat plasma. Application of this assay to the determination of the bolus dose plasma kinetics and disposition of 2 mg/kg CPE-C in rats is illustrated. This method is amenable to partial automation and is well-suited for the analysis of clinical samples.
Science | 1989
Robert Yarchoan; Hiroaki Mitsuya; Rose V. Thomas; James M. Pluda; Neil R. Hartman; Carlo Federico Perno; Kathy S. Marczyk; Jean-Pierre Allain; David G. Johns; Samuel Broder
Journal of Experimental Medicine | 1988
C F Perno; Robert Yarchoan; David A. Cooney; Neil R. Hartman; S Gartner; M Popovic; Zhang Hao; T L Gerrard; Yvonne A. Wilson; David G. Johns
Molecular Pharmacology | 1988
Zhang Hao; David A. Cooney; Neil R. Hartman; Carlo Federico Perno; A Fridland; A L DeVico; M G Sarngadharan; Samuel Broder; David G. Johns
Molecular Pharmacology | 1990
Zhang Hao; David A. Cooney; David Farquhar; Carlo Federico Perno; K. Zhang; R. Masood; Yvonne A. Wilson; Neil R. Hartman; Jan M. R. Balzarini; David G. Johns
Blood | 1992
Carlo-Federico Perno; David A. Cooney; Wen-Yi Gao; Zhang Hao; David G. Johns; Andrea Foli; Neil R. Hartman; Raffaele Calio; Samuel Broder; Robert Yarchoan
AIDS Research and Human Retroviruses | 1990
Neil R. Hartman; David G. Johns; Hiroaki Mitsuya
Clinical Infectious Diseases | 1990
Robert Yarchoan; Hiroaki Mitsuya; James M. Pluda; Katby S. Marczyk; Rose V. Thomas; Neil R. Hartman; Pim Brouwers; Carlo-Federico Perno; Jean-Pierre Allain; David G. Johns; Samuel Broder