Roderick D. Macgregor
University of California, San Francisco
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Featured researches published by Roderick D. Macgregor.
Pharmaceutical Research | 1986
C. Anthony Hunt; Roderick D. Macgregor; Ronald A. Siegel
A physiologically based model is presented to aid prediction of the pharmacological benefits to be derived from the administration of a drug as a targeted drug–carrier combination. An improvement in the therapeutic index and an increase in the therapeutic availability are the primary benefits sought. A measure of the former is obtained from the value of the drug targeting index, a newly derived parameter. Both the drug targeting index and the therapeutic availability are directly calculable. The minimum information needed for approximating both parameters is the candidate drugs total-body clearance and some knowledge of the target sites anatomy and blood flow. Drugs with high total-body clearance values that are known to act at target tissues having effective blood flows that are small relative to the blood flow to the normal eliminating organs will benefit most from combination with an efficient, targeted carrier. Direct elimination of the drug at the target site or at the tissue where toxicity originates dramatically improves the drug targeting index value. The fraction of drug actually released from the carrier at both target and nontarget sites can radically affect index values. In some cases a 1% change in the fraction of the dose delivered to the target can result in a 50% change in the drug targeting index value. It is argued that most drugs already developed have a low potential to benefit from combination with a drug carrier. The approach allows one to distinguish clearly those drugs that can benefit from combination with targeted in vivo drug carriers from those drugs that cannot.
Pharmaceutical Research | 1985
Koichiro Hirano; C. Anthony Hunt; Anne Strubbe; Roderick D. Macgregor
Tumor cells often metastasize through lymphatic channels. It follows that localization of antitumor agents in the lymphatics may be therapeutically beneficial. This study determines the extent to which lipid composition controls lymphatic transport of a model compound (14C-sucrose) in liposomes following intraperitoneal administration in rats. All liposomes tested had mean diameters of approximately 0.2 µm. Liposomes were administerd to thoracic duct cannulated rats, and 14C was quantified in thoracic lymph, several lymph nodes, blood, urine, and peritoneal wash. Changing liposome composition altered the rate of absorption of 14C from the peritoneal cavity, stability in biological fluids, and the relative ability of liposomes to be retained by lymph nodes. Stability in biological fluids (plasma and lymph) appeared to be a reasonable predictor of observed lymph node recovery. Direct measures of lymph node level alone were poor measures of the ability of liposomes to function as prototypal lymphatic drug carriers. Neutral liposomes were better at reaching the general circulation following absorption from the peritoneal cavity.
Journal of Pharmacokinetics and Biopharmaceutics | 1991
Ronald A. Siegel; Roderick D. Macgregor; C. Anthony Hunt
A simple stochastic recirculatory formalism is used to compare models of regional drug delivery due to Huntet al. and Boddy and Aarons. It is shown that these two models are equivalent when regional delivery is ideal. The latter model has the advantage of simplicity. However, the former model appears more useful in relating predictions to experimentally accessible quantities. Neither model is sufficiently general to cover all possible topologies of regions associated with drug response and toxicity. Knowledge of this topology is essential in determining the drug targeting index. The underlying assumptions of the models are discussed, and situations where these assumptions may break down are identified. Finally, it is noted that the analysis of regional delivery may also apply to metabolite and prodrug kinetics.
Artificial Cells, Blood Substitutes, and Biotechnology | 1990
Roderick D. Macgregor; C. Anthony Hunt
Factors governing nonspecific reticuloendothelial system (RES)-detectability are largely unknown. Will a liposome that mimics the lipid composition of the outer leaflet of the erythrocyte membrane be invisible to the RES? On both experimental and theoretical grounds we believe the answer is no, in part because 1) sorption of proteins is believed to be important in determining RES uptake, 2) a membrane skeleton is apparently necessary to inhibit protein sorption into erythrocyte membranes and 3) Neohemocytes (a liposome encapsulated hemoglobin product) currently lack a membrane skeleton. Neohemocytes with erythrocyte outer leaflet lipid composition do have extended circulation half-times, but these are at least two orders of magnitude shorter than the circulation half-times of erythrocytes. How might a membrane skeleton modulate RES-detectability? Can avoidance of opsonization result in part from the properties of the membrane skeleton? If so, then how? To explore and quantify such questions we have developed a theoretical, statistical-thermodynamic model of protein binding into membranes. It predicts that the membrane area available for rapid lateral diffusion is critically important in controlling the amount of sorbed protein per unit area, and that a membrane skeleton can reduce a proteins sorption by several orders of magnitude. Based on theoretical results, we offer a speculative model for the detection of non-self lipid bilayers by the RES.Factors governing nonspecific reticuloendothelial system (RES)-detectability are largely unknown. Will a liposome that mimics the lipid composition of the outer leaflet of the erythrocyte membrane be invisible to the RES? On both experimental and theoretical grounds we believe the answer is no, in part because 1) sorption of proteins is believed to be important in determining RES uptake, 2) a membrane skeleton is apparently necessary to inhibit protein sorption into erythrocyte membranes and 3) Neohemocytes (a liposome encapsulated hemoglobin product) currently lack a membrane skeleton. Neohemocytes with erythrocyte outer leaflet lipid composition do have extended circulation half-times, but these are at least two orders of magnitude shorter than the circulation half-times of erythrocytes. How might a membrane skeleton modulate RES-detectability? Can avoidance of opsonization result in part from the properties of the membrane skeleton? If so, then how? To explore and quantify such questions we have developed a theoretical, statistical-thermodynamic model of protein binding into membranes. It predicts that the membrane area available for rapid lateral diffusion is critically important in controlling the amount of sorbed protein per unit area, and that a membrane skeleton can reduce a proteins sorption by several orders of magnitude. Based on theoretical results, we offer a speculative model for the detection of non-self lipid bilayers by the RES.
Archive | 1992
Serge Guzy; C. Anthony Hunt; Roderick D. Macgregor
A new methodology allows one to directly estimate a dependent variable’s probability density function without the need to randomly generate large data sets via Monte Carlo simulations. The approach can be used independently of both the deterministic pharmacokinetic model and the distributions of estimated parameter values. An important feature is that the method can be used in cases of either independent either correlated parameters.
MRS Proceedings | 1987
Roderick D. Macgregor; Noel Taylor; C. Anthony Hunt
The unique procedure developed for forming artificial red cells (Science 230, 1165, 1985) allows encapsulation of proteins to concentrations in excess of 20g%. The procedure requires a hypotonic starting solution, whereas the final suspension is equilibrated at 300 mOsm. Hemoglobin (Hb) was one of several proteins encapsulated. The procedure is based on emulsion formation and subsequent evaporation of the nonaqueous phase, a common liposome-formation procedure, but has unique features. The densities of the phases are matched by adding a Freon. The emulsion is formed using conditions that eliminate protein denaturation. This research was designed to evaluate the fine structure at each critical stage using thin section electron microscopy. The results revealed remarkable, previously unseen detail that raises questions about the variety of properties that can be engineered into lipid bilayer structures. The initial emulsion was nonclassical. Submicron particles in large relative numbers suggested a minimal surface tension difference between the two phases. After nearly complete evaporation of the nonaqueous phase, “microcapsule” particles were present but their architecture showed little in common with classical liposomes; there was no evidence of bilayer membranes. Following extrusion, a slow increase in the osmolality to 300 mOsm dramatically altered the architecture of the microcapsules: The encapsulated protein concentration increased, and lipid bilayer membranes were formed. The resulting “liposomes” were often chambered rather than having concentric bilayer structures. Two closely opposed bilayers surrounding a volume of protein solution was a common structure.
Journal of Biological Chemistry | 1994
Murali Ramanathan; M Lantz; Roderick D. Macgregor; M R Garovoy; Hunt Ca
Transplantation | 1994
Murali Ramanathan; Marianne Lantz; Roderick D. Macgregor; Bing Huey; S. Tam; Ying Li; Marvin R. Garovoy; C. A. Hunt
Antisense research and development | 1993
Murali Ramanathan; Roderick D. Macgregor; C. Anthony Hunt
Journal of Pharmaceutical Sciences | 1985
C. Anthony Hunt; Roderick D. Macgregor