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Biomedical subjects

R L Dedrick

Publications and source records attributed to R L Dedrick.

At least 91 records · Page 5Linked to original sources
PubMed1985

Reduced systemic drug exposure by combining intra-arterial chemotherapy with hemoperfusion of regional venous drainage.

Four patients with malignant cerebral gliomas received 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) into the internal carotid artery (ICA) while the ipsilateral jugular drainage was pumped extracorporeally through a hemoperfusion cartridge containing a nonionic adsorbant resin. Each patient received 220 mg/sq m BCNU, infused over 45 minutes through a toposcopic catheter positioned with the tip in the ICA beyond the origin of the ophthalmic artery. Jugular blood was pumped extracorporeally at 300 ml/min through a large-bore catheter in the jugular bulb. Plasma samples were obtained for BCNU measurement at frequent intervals from the right atrium. During a separate treatment, 6 weeks before or after the hemoperfusion treatment, the same dose of BCNU was infused into the ICA and atrial samples were obtained on a similar schedule. Hemoperfusion of the jugular blood during intracarotid infusion reduced the systemic exposure by 56% to 87% and increased total body clearance of BCNU by two- to eightfold. The calculated pharmacokinetic advantage (brain:body exposure ratio) was between 21 and 55:1 when the combined treatment was used.

Adolescent↗
PubMed1985

Arterial drug infusion with extracorporeal removal. II. Internal carotid carmustine in the rhesus monkey.

During cancer chemotherapy by intra-arterial drug administration, systemic toxicity often limits the tolerable dose. We evaluated the pharmacokinetic advantage obtained by infusing carmustine (BCNU) into the internal carotid artery during BCNU removal from the blood from the perfused region by hemoperfusion. A hemoperfusion column (XR-010, Extracorporeal Medical Specialties) was shown to remove BCNU quantitatively from sheep blood flowing at 300 ml/minute when the drug was infused at 13 mg/minute for 30 minutes. Under general anesthesia, adult rhesus monkeys underwent catheterization of the internal carotid artery and placement of a catheter in the ipsilateral jugular vein at its junction with the sigmoid sinus. BCNU (10 mg/kg) was infused over 20 minutes while blood was pumped from the jugular vein through a small column and back into the inferior vena cava. The procedure reduced systemic exposure by 46%-84% compared with iv infusion of the same dose. Brain-to-systemic exposure ratios ranged from 18:1 to 87:1, depending on the pump flow rate and method of calculation. Hematopoietic toxicity was prevented. It is suggested that tumor exposure to BCNU comparable to that associated with very high tumor cell kill in vitro may be feasible with little or no systemic toxicity.

Animals↗
PubMed1985

Theoretical and experimental bases of intraperitoneal chemotherapy.

Pharmacokinetic theory predicts that a large and potentially exploitable concentration difference occurs between the peritoneal cavity and the plasma after many anticancer drugs are administered intraperitoneally in large volume. Unresolved issues remain, particularly concerning the depth of penetration of drugs into tumor nodules growing on peritoneal surfaces. Recent studies in the rat showed a steep concentration gradient of small marker molecules in a variety of normal tissues. The concentration in the stomach and small and large intestines decreased to 10% of the value at the serosal surface in about 0.5 mm or less. Human serum albumin showed deeper penetration, particularly in the diaphragm and anterior abdominal wall.

Absorption↗
PubMed1984

Pharmacokinetics of PCBs.

The pharmacokinetics of PCBs are complicated by numerous factors, not the least of which is the existence of up to 209 different chlorinated biphenyls. Whereas all PCB congeners are highly lipophilic and most are readily absorbed and rapidly distributed to all tissues, PCBs are cleared from tissues at very different rates, and the same congeners may be cleared at different rates by different species. With the exception of special situations in which PCBs may be passively eliminated in lipid sinks, e.g. milk or eggs, clearance is minimal prior to metabolism to more polar compounds. Rates of PBC metabolism vary greatly with species and with the degree and positions of chlorination. Mammals metabolize these compounds most rapidly, but even among mammalian species rates of metabolism vary greatly. In all species studied, the more readily metabolized chlorinated biphenyls have adjacent unsubstituted carbon atoms in the 3-4 positions. Congeners that do not have adjacent unsubstituted carbon atoms may be metabolized very slowly and are therefore cleared very slowly. These PCBs not readily cleared concentrate in adipose tissue. A physiologic pharmacokinetic model best illustrates how the concentrations of PCBs in all tissues approach equilibrium with the blood and with one another. Thus, the model illustrates how a depot of PCBs in any tissue, e.g. adipose tissue, will result in exposure of all tissues in proportion to the respective tissue/blood ratios and the body burden. The disposition of a number of PCBs in the rate has been accurately described by a physiologic model, and the model has been extrapolated to predict the disposition of these same PCBs in the mouse (58). Therefore, the physiologic pharmacokinetic model is believed to offer the best opportunity to extrapolate data obtained with laboratory animals to predict the disposition of PCBs in other species, including man. Most of the parameters of a model of PCB disposition in man are available or could be estimated. The major limitation to the construction of such a model is the absence of accurate estimates of metabolic clearance of individual PCBs by man. Accurate estimates of metabolic clearance depend on development of suitable in vitro methods to accurately predict clearance in vivo.

Animals↗
PubMed1984

A distributed model of peritoneal-plasma transport: theoretical considerations.

Transport of water-soluble substances between the peritoneal cavity and the plasma was modeled with a distributed approach. The model includes diffusion and convection through tissue as well as membrane transport across blood capillaries, which are assumed to be distributed uniformly in the tissue. Lymphatic uptake via the diaphragm is also included. Transport in the remainder of the body is modeled by a system of compartments. The resulting system of mass balances and rate equations is solved numerically to provide predictions of peritoneal volume and concentrations in plasma, peritoneal fluid, and tissue surrounding the cavity. The model sensitivity is explored by varying key parameters to determine whether the changes would have a significant effect on model output. Key parameters include peritoneal surface area, tissue diffusivity, capillary permeability, tissue void fraction, and hydrostatic and osmotic pressures in the capillaries and interstitium.

Absorption↗
PubMed1984

Arterial drug infusion with extracorporeal removal. I. Theoretic basis with particular reference to the brain.

The pharmacokinetic advantage of intra-arterial drug administration can be improved if blood from the infused region is perfused through a suitable extracorporeal device. The extent of improvement depends on the blood flow to the device, the fraction of the vascular drainage that can be obtained, and the drug extraction by the device. A relatively simple equation is derived to assess the pharmacokinetic advantage and to define the governing parameters. Application of the theory to the treatment of brain tumors includes a discussion of the selection of an experimental animal and interpretation of results. It is suggested that tumor exposure to carmustine comparable to that associated with very high tumor cell kill in vitro may be feasible with little or no systemic toxicity.

Animals↗
PubMed1983

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.

Animals↗
PubMed1983

Distributed model for drug delivery to CSF and brain tissue.

Measurements of drug concentration in cerebrospinal fluid (CSF) provide the most accessible index of drug delivery to the brain. Our perception of the blood-brain barrier has been largely shaped by these measurements. A crucial question for the interpretation of these data is the nature of the relationships between drug concentration in CSF and the drug concentration profile in brain tissue. A distributed model for the delivery of drugs via plasma to brain tissue and CSF is presented, and the relationships between capillary exchange, tissue diffusion, and CSF turnover rate are explored. The effects of blood-brain barrier disruption on tissue and CSF concentrations are also simulated.

Animals↗
PubMed1982

Contribution of lungs to total body clearance: linear and nonlinear effects.

The contribution of the lungs to the total body clearance of drugs is examined in a framework that emphasizes their anatomical position. For intravenous administration, the lung is the only organ other than blood that can account for a total body clearance in excess of the cardiac output. Systemic arterial drug concentration and tissue drug exposure are inversely proportional to total body clearance. Although the role of the lung has been overshadowed by that of the liver, several examples are presented to demonstrate that relatively small amount of pulmonary activity can produce a large reduction in systemic arterial drug concentration. For oral administration, first-pass elimination by the liver and lungs in series results in a synergistic increase in total body clearance. Nonlinear effects caused by saturation of elimination pathways are also examined. Increased emphasis on experimental investigation of the pulmonary contribution is warranted, especially for drugs with high apparent clearance.

Animals↗
PubMed1982

Concentration-dependent disappearance of fluorouracil from peritoneal fluid in the rat: experimental observations and distributed modeling.

The rate of disappearance of fluorouracil from peritoneal fluid has been experimentally measured and mathematically modeled. The experimental data were obtained following the instillation of 50 ml of dialysis fluid which contained an initial fluorouracil concentration ranging from 24 microM to 12 mM. The rate of disappearance was strongly dependent upon concentration. A distributed model has been formulated which incorporates concepts of diffusion with saturable metabolism and nonsaturable capillary uptake in the tissue surrounding the peritoneal fluid. This model successfully describes the experimental observations and also suggests that the effective penetration depth into tissue is highly dependent upon concentration.

Animals↗
PubMed1981

Enteric transport of chlordecone (Kepone) in the rat.

Disposition of chlordecone (Kepone) in the rat is quantitated. Particular attention is devoted to the role of the intestinal tract in excretion, as well as absorption, of the parent form of the halogenated pesticide. A detailed physiological pharmacokinetic model for the GI tract is presented in which the organs are segmented into a series of well-mixed compartments representing stomach, small intestine, cecum, and large intestine. The model is applied to the early time behavior of data from the following two types of studies in the rat: (1) the movement of a nonabsorbable tracer along the GI tract, and (2) the enteric transport of parent chlordecone. Model parameter values for the gut wall permeability-area products for parent chlordecone determined for the rat are used to estimate the corresponding values for man based on scale-up considerations. The enhancement of excretion rates through use of orally administered adsorbents is discussed.

Animals↗
PubMed1981

Physiologic model for the pharmacokinetics of 2'deoxycoformycin in normal and leukemic mice.

A flow-limited physiologic mathematical model has been developed to describe the time course of 2'deoxycoformycin (2'dCF) concentrations in the plasma and tissues of mice following iv and ip doses. Urinary excretion is modeled as a linear involving filtration and secretion, since kidney clearance exceeded estimated glomerular filtration rate. Intracellular binding is described as the sum of linear nonspecific binding plus strong saturable binding to adenosine deaminase. Pharmacokinetic parameters are determined by a sequential optimization scheme in which each tissue is studied by means of a hybrid model. The model has been used to predict pharmacokinetic behaviour of 2'dCF in both normal and leukemic mice, and model simulations are compared with published data.

Adenosine Deaminase↗
PubMed1981

Portal levels and hepatic clearance of 5-fluorouracil after intraperitoneal administration in humans.

Intrahepatic tumor is a major problem in clinical oncology. While direct intravascular infusions provide high local drug concentrations and variable rates of tumor response, they are limited by technical considerations and complications. In this study, we have tested whether high portal venous and hepatic arterial concentrations of 5-fluorouracil (5-FUra) can be achieved by administering drug via peritoneal dialysis. Four patients with metastatic colon carcinoma had a Tenckhoff catheter surgically implanted. During dialysis therapy with 4 mM 5-FUra, simultaneous samples of peritoneal fluid and of portal venous, hepatic venous, and peripheral venous, and arterial blood were obtained, and 5-FUra concentrations were determined. Mean peak portal vein drug concentrations were 60 microM and exceeded the measured concentrations in the other vessels. Total drug exposures as measured by concentration x time (mM x min) during Exchange 1 were: portal, 3.8 +/- 0.65; hepatic vein, 0.97 +/- 0.44; peripheral vein, 0.90 +/- 0.32; and arterial, 1.1 +/- 0.26. During Exchange 7, total drug exposures were: portal, 6.3 +/- 1.4; hepatic vein, 2.5 +/- 1.3; peripheral vein, 2.3 +/- 1.1; and arterial, 2.7 +/- .85. The fraction of i.p. drug that exited the peritoneal cavity through the portal venous system ranged from 0.29 to 1.0. This variation resulted in part from uncertainty in estimating portal blood flow and gastrointestinal drug elimination. Calculated hepatic extraction was 67% (range, 0.23 to 0.89). Extrahepatic metabolism was demonstrated. Measured 5-FUra concentrations compared favorably to values predicted by a pharmacokinetic model for 5-FUra. Dialysis therapy (i.p.) with 5-FUra provides a means of achieving high drug concentrations for treating both i.p. and intrahepatic tumor. Further clinical testing of this route of administration is warranted.

Adult↗
PubMed1981

High-volume intraperitoneal chemotherapy with methotrexate in patients with cancer.

The use of high-volume i.p. chemotherapy with methotrexate (7.5 to 50 microM methotrexate administered via peritoneal dialysis technique) was studied in four patients with ovarian cancer and one patient with malignant melanoma. All had tumor localized to the peritoneal cavity or liver. Methotrexate concentration in the peritoneum could be maintained 18- to 36-fold higher than corresponding plasma concentrations using this method, plasma levels remaining in the range of 0.2 to 3 microM. While local toxicity was generally limited and manageable, mild aseptic peritoneal irritation was commonly seen, and one episode of bacterial peritonitis did occur. Because of the concentration difference between peritoneum and the systemic circulation, systemic toxicity was moderate with only six of 29 treatment cycles resulting in myelosuppression. No definite therapeutic benefit was seen, but the tumors of four of five patients had demonstrated resistance to a methotrexate-containing chemotherapeutic regimen prior to this study. Further investigation of this novel treatment modality is warranted. In addition, this study provides the first measurement of peritoneal methotrexate clearance and the ratio of peritoneal in total body clearance.

Adenocarcinoma↗
PubMed1980

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 15 microM 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.

Administration, Oral↗
PubMed1980

Species similarities in pharmacokinetics.

There are many well documented similarities in the anatomy and physiology of mammalian species. There are also numerous examples in which the equilibrium distribution of foreign chemicals in the body appears to follow principles of thermodynamic partitioning with relatively minor interspecies variations to be expected. Information on metabolic pathways and their kinetic characteristics can be obtained from a variety of in vitro systems. It may be possible to use such information in pharmacokinetic models that incorporate existing knowledge and judgment to predict pharmacokinetics in intact animals including man.

Animals↗
PubMed1980

Phase I and pharmacological studies of 5-fluorouracil administered intraperitoneally.

A Phase I study was conducted of 5-fluorouracil administered i.p. in a 2-liter volume of 1.5% Inpersol. The drug was administered via Tenckhoff peritoneal dialysis catheters to ten patients with tumors confined to the i.p. space. Dialysis concentrations ranged from 5 micro M to mM. Complications of the dialysis procedure alone included mild abdominal discomfort and 2 cases of gram-negative bacterial peritonitis, both easily controlled with antibiotics. 5-Fluorouracil caused the same pattern of toxicity as when administered by other routes. There was no local or central nervous system toxicity. Dose-limiting toxicity included pancytopenia and mucositis at a dialysis concentration of 4.5 to 5 mM administered for eight consecutive 4-hr exchanges. There were two documented responses in eight evaluable patients. 5-Fluorouracil concentrations were measured by high-pressure liquid chromatography. Peritoneal fluid concentrations decline in a first-order fashion with a half-life of 1.6 hr. The mean permeability area product was 14 ml/min. A mean of 82% of drug was absorbed in 4 hr. Plasma levels rise over the first 30 to 45 min and decline in a nonlinear fashion. Plasma levels are substantially lower than are peritoneal fluid levels. Mean 4-hr peritoneal fluid concentration was 298 times the simultaneously measured plasma levels. Total body clearance ranged from 0.9 to 15 liters/min and declined with increasing dialysate concentration. We conclude the i.p. route is a relatively safe way to deliver high concentrations and large amounts of drug to the i.p. cavity with a significant pharmacological advantage over conventional routes of administration.

Colonic Neoplasms↗