Robert L. Dedrick

Cell culture on artificial capillaries: an approach to tissue growth in vitro.

Artificial capillaries perfused with culture medium provide a matrix in which cells can attain tissue-like densities in vitro. Products secreted into the medium can be measured as indicators of cell function or may be recovered for other purposes without disturbing the culture.

Animal scale-up.

Animal scale-up is discussed as a formal approach to drug distribution in the body which permits consideration of scale through the individual processes that occur. Some of these are physical, such as blood flows, tissue binding, and kidney clearances. Others are chemical, such as metabolic reactions. The physical processes often vary quite predictably among mammalian species, and much is known about these independent of any chemical reactions. Certain metabolic reactions vary greatly and unpredictably among species. The physical and chemical processes interact so that the relationship of the pharmacokinetics of any given drug between one species and another may be quite straightforward or it may be rather obscure unless the correct interaction is perceived. Methotrexate pharmacokinetics are reviewed in discussing the use of animal scale- up for a drug where only physical processes need be considered. Problems involving metabolism are illustrated for thiopental and cytosine arabinoside.

Nonlinear pharmacokinetic models for 5-fluorouracil in man: Intravenous and intraperitoneal routes

A two‐compartment physiologic pharmacokinetic model has been developed for 5‐fluorouracil (5FU). This model, which incorporates saturable whole body clearance, satisfactorily predicts disappearance kinetics after an intravenous bolus and steady‐state levels during constant intravenous infusions. A half‐saturating concentration (KM) of 15μM was determined by comparison of model simulations with literature data. Both hepatic and extrahepatic elimination can be inferred for 5FU, but the exact anatomic or compartmental location of the clearance cannot be determined from the available clinical data. The effect of venous and arterial plasma sampling is discussed. This model has been extended to include intraperitoneal and oral administration of 5FU by the addition of peritoneal fluid and liver compartments.

Quantitative Examination of Tissue Concentration Profiles Associated with Microdialysis

Abstract: Spatial solute concentration profiles resulting from in vivo microdialysis were measured in rat caudate‐putamen by quantitative autoradiography. Radiolabeled sucrose was included in the dialysate, and the tissue concentration profile measured after infusions of 14 min and 61.5 min in an acute preparation. In addition, the changes in sucrose extraction fraction over time were followed in vivo and in a simple in vitro system consisting of 0.5% agarose. These experimental results were then compared with mathematical simulations of microdialysis in vitro and in vivo. Simulations of in vitro microdialysis agreed well with experimental results. In vivo, the autoradiograms of the tissue concentration profiles showed clear evidence of substantial differences between 14 and 61.5 min, even though the change in extraction fraction was relatively small over that period. Comparison with simulated results showed that the model substantially underpre‐dicted the observed extraction fraction and overall amount of sucrose in the tissue. A sensitivity analysis of the various model parameters suggested a tissue extracellular volume fraction of approximately 40% following probe implantation. We conclude that the injury from probe insertion initially causes disruption of the blood‐brain barrier in the vicinity of the probe, and this disruption leads to an influx of water and plasma constituents, causing a vasogenic edema.

Quantitative Microdialysis: Analysis of Transients and Application to Pharmacokinetics in Brain

Abstract: The behavior of a microdialysis probe in vivo is mathematically described. A diffusion‐reaction model is developed that not only accounts for transport of substances through tissues and probe membranes but also accounts for transport across the microvasculature and metabolism. Time‐dependent equations are presented both for the effluent microdialysate concentration and for concentration profiles about the probe. The analysis applies either to measuring the tissue pharmacokinetics of drugs administered systemically, or for sampling of endogenously produced substances from tissue. In addition, an expression is developed for the transient concentration about the probe when it is used as an infusion device. All mathematical expressions are found to be a sum of an algebraic and an integral term. Theoretical prediction of time‐dependent probe behavior in brain has been compared with experimental data for acetaminophen administered at 15 mg/kg to rats by intravenous bolus. Plasma and whole striatal tissue samples were used to describe plasma kinetics and to estimate a capillary permeability‐area product of 0.07 min‐1. Theoretical prediction of transient effluent dialysate concentrations exhibited close agreement with experimental data over 60 min. Terminal decline of the dialysate effluent concentration was slightly overestimated but theoretical concentrations still lay within the 95% confidence interval of the experimental data at 112 min. Microvasculature transport and metabolism play major roles in determining microdialysate transient responses. Extraction fraction (recovery) has been shown to be a declining function in time for five probe operating conditions. High rates of metabolism and/or capillary transport affect the time required to approach steady‐state extraction, shortening the time as the rates increase. Conversely, for substances characterized by low permeabilities and negligible metabolism, experimental situations exist that are predicted to have very slow approaches to microdialysis steady state.

High volume intraperitoneal chemotherapy ("belly bath") for ovarian cancer. Pharmacologic basis and early results.

SummaryThe currently accepted therapies for ovarian cancer have produced only limited numbers of extended complete remissions in advanced-stage disease. Studies of high-volume intraperitoneal chemotherapy have been initiated to define the toxicology, pharmacokinetics, and the therapeutic effectiveness of this treatment modality. This technique has been virtually ignored until recently, because little success has been achieved with it except in one study (Rutledge, 1966), in which large intraperitoneal fluid volumes were used. The general lack of success probably reflects inadequate attention to physiologic and pharmacologic principles of drug distribution and absorption in a space as large as the peritoneal cavity. Biomedical engineers, pharmacologists, and clinicians at the NCI have cooperated in the development of a rational chemotherapy for ovarian cancer. Following mathematical pharmacokinetic modeling and toxicologic studies in rat, a Phase I clinical trial of intraperitoneal methotrexate administered in large volumes of dialysis fluid was initiated. Results in three patients confirm the practicality of this approach, and further investigation is warranted.

Pharmacokinetics of 1-β-d-arabinofuranosylcytosine (Ara-C) deamination in several species

Abstract The pharmacokinetics of 1-β- d -arabinofuranosylcytosine (Ara-C) and 1-β- d -arabinofuranosyluracil (Ara-U) are related to enzyme kinetics in vitro in mice, monkeys, dogs and humans by means of a mathematical model. The model is physiologic and permits the incorporation of chemical reactions in appropriate anatomic sites with kinetic characteristics of their local environment. A lean tissue compartment plays an important role as a reservoir. The kidney clearance of Ara-C exhibits essentially the same variation with body weight as inulin.

In vitro-in vivo correlation of drug metabolism-deamination of 1-β-d-arabinofuranosylcytosine

Abstract A pharmacokinetic model is presented to permit rational use of enzyme activities and Michaelis constants determined in vitro . It is based on physiologic and anatomic principles and is validated by comparison of predicted urinary excretion of 1-β- d -arabinofuranosylcytosine and its metabolite with published data from humans. Model predictions are compared with new data on plasma concentrations of the drug and its metabolite as functions of time after intravenous pulse doses of 1–2 and 86 mg/kg of the parent compound.

Physiological model for the pharmacokinetics of 2,3,7,8-tetrachlorodibenzofuran in several species

A flow-limited physiological model was developed to describe the time course of 2,3,7,8-tetrachlorodibenzofuran (TCDF) in the blood and tissues of rats, mice, and monkeys. The liver showed the greatest tendency to concentrate the material with tissue-to-blood distribution coefficients ranging from 30 in the monkey to 130 in the mouse. TCDF was also concentrated in the fat with tissue-to-blood distribution coefficients between 25 and 40 in all species. TCDF was eliminated by metabolism followed by excretion primarily to the feces. Urinary excretion was a minor route of elimination in all species. Metabolism was modeled as a linear process occurring in the liver. Intrinsic metabolic clearances ranged from 0.45 ml/min/kg in the monkey to 2.8 ml/min/kg in one species of mice. Fecal excretion of TCDF-derived radioactivity can be simulated with a series of well-mixed compartments which receive input of metabolites in the bile.

A pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin as primary treatment of patients with small-volume residual ovarian cancer.

Purpose: Because intraperitoneal (i.p.) therapy may provide a therapeutic advantage and because hyperthermia enhances carboplatin (CBDCA) cytotoxicity, we evaluated the feasibility, toxicity, and pharmacokinetics of CBDCA given via continuous hyperthermic peritoneal perfusion (CHPP) in patients with small-volume residual ovarian cancer. Patients and Methods: Six patients underwent optimal cytoreductive procedures (residual disease ≤5 mm) as initial treatment of stages II and III epithelial ovarian adenocarcinoma. All patients received a 90-min CHPP at a CBDCA dose of 800–1200 mg/m2, with the perfusate being recirculated rapidly from a reservoir through a heat exchanger, resulting in i.p. temperatures of 41–43 °C. Plasma, perfusate, and urine samples were collected and platinum was quantified by flameless atomic absorption spectrophotometry. Results: At no time did any patients core temperature exceed 40 °C. Peak perfusate platinum concentrations were 8- to 15-fold higher than peak ultrafilterable plasma concentrations. The permeability-area product was extremely high and variable (14–90 ml/min), resulting in a regional advantage of 1.9–5.3. The percentage of the dose absorbed ranged widely from 27% to 77%. Dose-limiting hematologic toxicity was observed at a dose of 1200 mg/m2 and this was associated with a CBDCA AUC in plasma of 11 mg min ml−1. Conclusions: CHPP with CBDCA was safely given to three patients at a dose of 800 mg/m2, and dose-limiting hematologic toxicities observed at 1200 mg/m2, correlated with the plasma CBDCA exposure established when lower doses of CBDCA are given systemically. The pharmacokinetic data are consistent with the expected effect of vigorous mixing on the exposed peritoneal surface area. Variable drug absorption and clearance make the prediction of systemic exposure highly uncertain. These findings may have important implications for novel therapies given i.p.