Showing papers in "Drug Metabolism Reviews in 1992"

Acyl glucuronides revisited: is the glucuronidation process a toxification as well as a detoxification mechanism?

Abstract: (1992). Acyl Glucuronides Revisited: Is the Glucuronidation Proces a Toxification as Well as a Detoxification Mechanism? Drug Metabolism Reviews: Vol. 24, No. 1, pp. 5-47.

Molecular aspects of paracetamol-induced hepatotoxicity and its mechanism-based prevention.

Abstract: (1992). Molecular Aspects of Paracetamol-Induced Hepatotoxicity and its Mechanism-Based Prevention. Drug Metabolism Reviews: Vol. 24, No. 3, pp. 367-407.

The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions

Abstract: Evidence strongly suggests that many adverse drug reactions, including idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to reactive metabolites, are associated with a high incidence of adverse reactions. Most drugs can probably form reactive metabolites, but a simple comparison of covalent binding in vitro is unlikely to provide an accurate indication of the relative risk of a drug causing an idiosyncratic reaction because it does not provide an indication of how efficiently the metabolite is detoxified in vivo. In addition, the incidence and nature of adverse reactions associated with a given drug is probably determined in large measure by the location of reactive metabolite formation, as well as the chemical reactivity of the reactive metabolite. Such factors will determine which macromolecules the metabolites will bind to, and it is known that covalent binding to some proteins, such as those in the leukocyte membrane, is much more likely to lead to an immune-mediated reaction or other type of toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely and could lead to adverse reactions in almost any organ; however, most reactive metabolites have a short biological half-life, and although small amounts may escape the organ where they are formed, these metabolites are unlikely to reach sufficient concentrations to cause toxicity in other organs. Many idiosyncratic drug reactions involve leukocytes, especially agranulocytosis and drug-induced lupus. We and others have demonstrated that drugs can be metabolized by activated neutrophils and monocytes to reactive metabolites. The major reaction appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous acid is quite reactive, and therefore it is likely that many other drugs will be found that are metabolized by activated leukocytes. Some neutrophil precursors contain myeloperoxidase and the NADPH oxidase system, and it is likely that these cells can also oxidize drugs. Therefore, although there is no direct evidence, it is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia. This could involve direct toxicity or an immune-mediated reaction. These mechanisms are not mutually exclusive, and it may be that both mechanisms contribute to the toxicity, even in the same patient. In the case of drug-induced lupus, a prevalent hypothesis for lupus involves modification of class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of the Gastrointestinal Mucosa and Microflora in the Bioactivation of Dietary and Environmental Mutagens or Carcinogens

Abstract: (1992). Role of the Gastrointestinal Mucosa and Microflora in the Bioactivation of Dietary and Environmental Mutagens or Carcinogens. Drug Metabolism Reviews: Vol. 24, No. 4, pp. 425-492.

Xenobiotic biotransformation/bioactivation in organogenesis-stage conceptual tissues: implications for embryotoxicity and teratogenesis.

Abstract: (1992). Xenobiotic Biotransfor Mation/Bioactivation in Organogenesis-Stage Conceptal Tissues: Implications for Embryotoxicity and Teratogenesis. Drug Metabolism Reviews: Vol. 24, No. 2, pp. 195-238.

Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem.

Abstract: (1992). Comparative Pharmacokinetic Profile of Two Imidazopyridine Drugs: Zolpidem and Alpidem. Drug Metabolism Reviews: Vol. 24, No. 2, pp. 239-266.

Models of Hepatic Drug Elimination

Abstract: The liver is, by nature, heterogeneous. It contains a complex vascular network for blood flow and a stationary phase consisting of enzymes within parenchymal cells. Several physiological processes, therefore, may combine to give observed ranges in drug elimination. Net changes in concentration are a consequence of a series of steps: uptake of substrate into liver cells, enzymatic reactions within the cells, release of metabolites and unconverted substrate from the cells into the sinusoids, and the net flow of the perfusing medium in the vasculature. In addition, substrate binding to proteins in the blood and in the liver can influence hepatic elimination. An understanding of each of these processes is necessary to fully comprehend the overall process of drug elimination, and these processes must be accounted for, either individually or by grouping and approximation, if a model for drug elimination is to be developed. Existing models of hepatic elimination may be classified according to their treatment of mixing within the vasculature and whether or not the model explicitly accounts for mass transfer between the heterogeneous phases of the liver. Four major classes may be defined: 1. Nonparametric homogeneous models, which assume that either complete mixing or no mixing occurs within the vasculature of the organ. 2. Homogeneous mixing models, which allow for a range of mixing phenomena. 3. Heterogeneous micromixing models, which allow for mass transport between the cells and vasculature and describe mixing within the vasculature on a microscopic level. 4. Heterogeneous compartmental models, which also describe interphase mass transfer but assume complete mixing on a microscopic level, and therefore use a time and spatially averaged approach to model mixing. The utility of these models of hepatic elimination will be critically assessed based upon (1) their ability to account for the influence of the aforementioned physiological processes upon elimination; (2) the data requirements of the model, in addition to its mathematical complexity and ease of use; and (3) the range of compounds and metabolites which may be described using the model.

Pharmacokinetics: Philosophy of Modeling

Abstract: Generally speaking, there are two extremes of scientific personality types: sharpeners and levelers. Sharpeners, highly attuned to system differences and nuances, and always alert to distinctions, try hard to let nothing slip by them unnoticed. Levelers, on the other hand, attempt to submerge system differences, reveal uniform patterns, and condense disparate elements. This paper is one leveler's attempt to address the following philosophical questions confronting pharmacokinetic modelers: (1) What is the nature of reality? (2) What is a model? (3) Why do we model? (4) What are the different types of models? (5) How do we model? (6) What are the properties and characteristics of models? (7) How do we evaluate models? (8) What are some of the tricks and traps of modeling? And (9), what are some of the psychological characteristics of modelers?

Lead-induced cell proliferation and organ-specific tumorigenicity.

Abstract: While lead acetate is a renal carcinogen in rodent studies, the mechanism by which it induces cancer has not been established. This report proposes that the enhanced susceptibility of renal tubular epithelial cells to lead-induced mitogenicity at the levels comparable to those administered in the cancer bioassay may contribute to the carcinogenic response seen in this target organ. Of relevance is that the nonresponsiveness of the liver to lead-induced carcinogenicity was associated with significantly less capacity (i.e., 675-fold) of lead to induce the mitogenic response in the rodent liver.

Mink as a predictive model in toxicology

Abstract: (1992). Mink as a Predictive Model in Toxicology. Drug Metabolism Reviews: Vol. 24, No. 4, pp. 559-578.

Pharmacology of second messengers : a critical appraisal

Abstract: (1992). Pharmacology of Second Messengers: A Critical Appraisal. Drug Metabolism Reviews: Vol. 24, No. 2, pp. 125-194.

Carl Paxson Sherwin, American pioneer in drug metabolism.

Abstract: (1992). Carl Paxson Sherwin, American Pioneer in Drug Metabolism. Drug Metabolism Reviews: Vol. 24, No. 4, pp. 493-530.