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Biomedical subjects

R L Dedrick

Publications and source records attributed to R L Dedrick.

At least 109 records · Page 6Linked to original sources
PubMed1979

Pharmacokinetics of halogenated hydrocarbons.

Pharmacokinetic modeling is being applied to chemicals posing health hazards because of their presence as contaminants in our environment. This paper presents a rationale for constructing mathematical models based on anatomic and physiological principles. Pharmacokinetic investigations incorporating such models are illustrated for two halogenated hydrocarbons that exhibit different patterns of disposition in the rat: 2,2',4,4',5,5'-hexachlorobiphenyl and Kepone. The models permit interspecies comparison and prediction of normal pharmacokinetic behavior and alterations induced by intervention measures. As an example a theoretical limit is predicted in the case of a treatment for Kepone poisoning involving oral administration of adsorbents.

Animals↗
PubMed1979

In vivo methotrexate transport in murine Lewis lung tumor.

Methotrexate uptake by murine Lewis lung tumor was measured in vivo over a wide dose range. The data were analyzed according to a model previously developed for tissues in which methotrexate uptake is rate limited by transport across the cell membrane. Methotrexate transport in this tumor followed Michaelis-Menten kinetics with a rate constant for permeability (k/K) of 0.012 min-1. The methotrexate binding capacity of dihydrofolate reductase in the tumor was not exceeded at any dose studied. A low membrane permeability in conjunction with a high dihydrofolate reductase level explains the resistance of this tumor to methotrexate.

Animals↗
PubMed1978

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

The 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.

Animals↗
PubMed1978

Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer.

Evidence from the peritoneal dialysis literature suggests that the peritoneal permeability of a number of hydrophilic anticancer drugs may be considerably less than plasma clearance. Pharmacokinetic calculations indicate that such drugs administered ip in large volumes are expected to maintain a significantly greater concentration in the peritoneal space than in the plasma. This concentration difference offers a potentially exploitable biochemical advantage in the treatment of patients with presumed microscopic residual ovarian cancer confined to the peritoneal cavity.

Antineoplastic Agents↗
PubMed1977

The construction of a pharmacokinetic model for the disposition of polychlorinated biphenyls in the rat.

The construction of a preliminary pharmacokinetic model for the distribution, long-term storage sites, excretion, and metabolism of selected polychlorinated biphenyls (PCBs) in the rat is described. Following intravenous administration of radioactive PCBs, several metaboiltes of each PCB isomer were detected in urine or feces, excreted primarily as glucuronide conjugates. The relative and absolute amount of metabolites excreted depended upon the degree of chlorination and the position of the chlorine on the biphenyl molecule. Concerning long-term storage sties, an unanticipated finding was accumulation in skin, as revealed by the particularly long half-life of the 6-CB isomer in skin. A flow diagram of the model is presented, as are the differential equations, solved by computer for a given dose schedule, for the individual mass balances on parent and metabolite in each of the compartments that represent the organs or regions in which the concentration is assumed to be uniform. Low-level, long-term doses of PCBs produce a variety of toxicologic symptoms which appear only after long-time exposure. Such models should be useful in explaining and predicting the toxicities induced by exposure to PCBs and similar contaminants and the time required to reach a steady-state tissue concentration for given long-term doses.

Animals↗
PubMed1977

Wall shear stress distribution in a model canine artery during steady flow.

The wall shear stress pattern was measured in a rigid plastic cast of a canine artery during steady flow by means of an electrochemical technique. The topographic distribution of shear stress is very nonuniform, with regions of high and low shear in close proximity. The steady shear stresses are highest at the leading edge of flow dividers and at the entrance regions to branch vessels. The shapes of the shear stress curves in the celiac branch are primarily a function of the ratio of branch flow to total aortic flow. However, the shapes of the shear stress curves in the adjacent anterior mesenteric branch remain the same for different anterior mesenteric branch flow ratios, although the shear increases with the branch flow ratio. An unstable pattern of flow separation and reattachment is found at the anterior mesenteric flow divider lip and remains localized to that region. A correlation is suggested between sites of high shear stress, extremes in the range of stress, and unstable stress patterns and sites at which atherosclerosis has been shown to develop.

Animals↗
PubMed1977

Antifolates: in vivo kinetic considerations.

The action of antimetabolites in vivo involves the consideration of several interrelated factors. If the mechanism of biochemical action is understood, the next items of priority are whether the active form of the drug gets to the site of action, its concentration at this site, the time course of removal of active drug from this site, and how these kinetics relate to the biochemical inhibition. Studies of antifolates represent some of the approaches used to further understand antimetabolite action in vivo. The interrelationships of blood flow, mixing volumes of tissue compartments, membrane resistance, binding of drug, binding site formation, transport competition, and biochemical kinetics of rate-limiting steps, substrate competition, and salvage pathways are considered from an in vivo point of view.

Animals↗
PubMed1977

A model for the kinetics of distribution of actinomycin-D in the beagle dog.

A pharmacokinetic model is presented for the distribution of actinomycin-D in the beagle dog. A simple, flow-limited model provides good simulations of the data at doses of 0.6 mg/m2 (0.03 mg/kg) and 2.7 mg/m2 (0.135 mg/kg) for most normal tissues. This implies that uptake of actinomycin-D in vivo is limited by tissue blood flow rate rather than by cell permeability. However, uptake by the testes is restricted by a blood-testis barrier, and a linear membrane-limited model is required to simulate the testis data. Linear binding of actinomycin-D to tissue is suggested by the fact that tissue concentrations are proportional to dose at least up to the lethal dose in dogs. The binding is also rapid and reversible as indicated by the tissue concentration curves which are parallel to the time course of the declining plasma curves.

Animals↗
PubMed1977

Clinical pharmacology of intrathecal methotrexate. I. Pharmacokinetics in nontoxic patients after lumbar injection.

Cerebrospinal fluid (CSF) and plasma methotrexate (MTX) concentrations were measured in 76 children and adults who received intrathecal MTX, 12 mg/m2 body surface area, without developing symptoms of lumbar puncture syndrome or drug-induced neurotoxicity. After an initial rapid redistribution of the injected drug, the mean antifolate value in the lumbar CSF declined in a biphasic manner with half-lives of 4.5 and 14 hours. In the plasma the mean MTX concentration reached a peak of 2 X 10(-7) M between 3 and 12 hours after injection and decreased biexponentially thereafter with half-lives of 5.5 and 24 hours. Pharmacokinetic analysis suggested that the predominant mode of MTX transfer from the central nervous system to the systemic circulation is bulk flow absorption of CSF with entrained drug. The two phases of disappearance from the lumbar CSF appear to result from interaction of the convective transport and diffusion between the CSF and brain extracellular fluid (and perhaps some intracellular sites).

Adolescent↗
PubMed1976

Device for constant Sc infusion of methotrexate: plasma results in mice.

An infusion device is described which permits sc infusion of methotrexate into mice at a constant rate. Physical characteristics of devices ranging in size from 0.27-mm internal diameter X 15 mm long to 1.95-mm internal diameter X 2 mm long are described. Plateau plasma concentrations of methotrexate (1 X 10(-8) M to 1 X 10(-5) M) achieved from infusion rates varying over three orders of magnitude (less than 1- greater than 100 mug/hour) are presented. These data are evaluated in terms of the known toxic effects and pharmacokinetic behavior of this drug.

Animals↗
PubMed1976

Distribution and disposition of platinum following intravenous administration of cis-diamminedichloroplatinum(II) (NSC 119875) to dogs.

cis-Diamminedichloroplatinum(II) is an antineoplastic drug that is undergoing a renewed clinical interest as a drug for use in combination regimens. In order to increase the understanding of the pharmacokinetics of this drug, the plasma clearance and organ distribution of platinum were followed in female beagle dogs treated with a single i.v. dose of cis-diamminedichloroplatinum(II). Plasma levels of platinum were determined by flameless atomic absorption spectrometry and showed a distinctly biphasic clearance pattern with a rapid-phase half-time of considerably less than 1 hr and a slow-phase half-time of nearly 5 days. During the first 4 hr after treatment, plasma levels fell by 90% while 60 to 70% of the applied dose was recovered in the urine. Sixteen tissues plus plasma, bile, and urine were routinely analyzed for platinum content. An easily measurable plasma concentration of platinum was still detectable 12 days after treatment, with no significant change in plasma concentration between Days 4 and 12. Initial concentrations of platinum were highest in organs of excretion, gonads, spleen, and adrenals but remained significantly elevated only in kidney, liver, ovary, and uterus, where a tissue: plasma ratio of 3 to 4 was maintained for as long as 6 days posttreatment. The apparent in vitro binding of platinum to dog plasma and to bovine serum albumin was studied by ultrafiltration and increased progressively during 48 hr of incubation at 37 degrees.

Animals↗
PubMed1975

The kinetics of methotrexate distribution in spontaneous canine lymphosarcoma.

A mathematical model is presented to simulate the time-dependent uptake of methotrexate in spontaneous canine lymphosarcomas in vivo. Blood flow ratew in these tumors are high so that transport to the tumor is limited by cell membrane resistance. A significant amount of rapidly exchangeable methotrexate appears to exist in extracellular space loosely bound to proteins or cell membranes. Transmembrane drug transport follows Michaelis-Menten kinetics, wigh the maximum facilitated transport ranging from 0.002 to 0.007 mug/min/ml for the separate tumors studied and a Michaelis constant for transport equal to 0.2 mug/ml. This is in the range of Michaelis constants reported for normal tissues in rats in vivo and in several cell linnes in vitro.

Animals↗