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Drug Entities (drug + entity)

Distribution by Scientific Domains
Medical Sciences50%
Life Sciences33%

Kinds of Drug Entities

  • new drug entity
    		•

    Selected Abstracts

    Functional interaction of intestinal CYP3A4 and P-glycoprotein

    FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004
    Kari T. Kivistö
    Abstract Intestinal CYP3A4-mediated biotransformation and active efflux of absorbed drug by P-glycoprotein are major determinants of bioavailability of orally administered drugs. The hypothesis that CYP3A4 and P-glycoprotein may act in concert to limit oral drug bioavailability is attractive from a theoretical point of view. Evidence in support of such an interplay between CYP3A4 and P-glycoprotein comes mainly from a limited number of in vitro and animal studies. Obviously, it is a challenging task to demonstrate in vivo in humans that the function of CYP3A4 and P-glycoprotein in enterocytes is complementary, and results to directly support this concept remain elusive. However, CYP3A4 and P-glycoprotein are clearly an integral part of an intestinal defence system to protect the body against harmful xenobiotics, and drugs that are substrates of both proteins often have a low bioavailability after oral administration. The functional interaction of intestinal CYP3A4 and P-glycoprotein warrants additional study. Further understanding this interplay would be potentially useful during drug development to solve bioavailability problems of new drug entities. [source]

    Polymers effect on estradiol partition coefficient between powdered human stratum corneum and water

    JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2002
    Ronald C. Wester
    Abstract Macromolecules have gained interest as drug entities unto themselves and as transport facilitators to alter initial phases of percutaneous absorption. Two macromolecular polymers (MW 2081 and 2565) were designed to hold cosmetics and drugs to the skin surface by altering initial chemical and skin partitioning. The effect of these polymers on the partition coefficient (PC) of estradiol with powdered human stratum corneum (PHSC) and water was determined. There was no statistically significant effect on the PC when the concentration of estradiol was increased 100-fold (0.028,2.8 ,g/mL), when the incubation time was increased from 0 to 24 h, or when PHSC was delipidized. The addition of a liphophilic polymer had no effect on the PC; however, the hydrophilic polymer showed a significant polymer concentration-dependent increase (p,<,0.01) in log PC for estradiol concentrations. Thus, a macromolecular chemical has the potential to alter the partitioning of chemical into the outer layers of skin, the first step in percutaneous absorption. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2642,2645, 2002 [source]

    Formed and preformed metabolites: facts and comparisons

    JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2008
    Professor K. Sandy Pang
    The administration of metabolites arising from new drug entities is often employed in drug discovery to investigate their associated toxicity. It is expected that administration of metabolites can predict the exposure of metabolites originating from the administration of precursor drug. Whether exact and meaningful information can be obtained from this has been a topic of debate. This communication summarizes observations and theoretical relationships based on physiological modelling for the liver, kidney and intestine, three major eliminating organs/tissues. Theoretical solutions based on physiological modelling of organs were solved, and the results suggest that deviations are expected. Here, examples of metabolite kinetics observed mostly in perfused organs that did not match predictions are provided. For the liver, discrepancies in fate between formed and preformed metabolites may be explained by the heterogeneity of enzymes, the presence of membrane barriers and whether transporters are involved. For the kidney, differences have been attributed to glomerular filtration of the preformed but not the formed metabolite. For the intestine, the complexity of segregated flows to the enterocyte and serosal layers and differences in metabolism due to the route of administration are addressed. Administration of the metabolite may or may not directly reflect the toxicity associated with drug use. However, kinetic data on the preformed metabolite will be extremely useful to develop a sound model for modelling and simulations; in-vitro evidence on metabolite handling at the target organ is also paramount. Subsequent modelling and simulation of metabolite data arising from a combined model based on both drug and preformed metabolite data are needed to improve predictions on the behaviours of formed metabolites. [source]

    Skeletal health: primate model of postmenopausal osteoporosis

    AMERICAN JOURNAL OF PRIMATOLOGY, Issue 9 2009
    S.Y. Smith
    Abstract Currently, the nonhuman primate is the most widely used large animal model to evaluate the safety and efficacy of new drug entities to treat or prevent estrogen-deficiency-induced bone loss and osteoporosis. Surgical ovariectomy (OVX) induces a state of high bone turnover and rapid bone loss establishing a new steady-state bone mass within 8,9 months. Many systems in the monkey are similar to humans, including skeletal and reproductive physiology and the immune system, making this a plausible model suitable to evaluate the effects of new bone drugs. The long-term sequelae following OVX and withdrawal of monthly exposure to cyclic reproductive hormones in older female monkeys (cynomolgus and rhesus) mimics estrogen depletion and postmenopausal bone loss occurring in women. Characterization of the primate model revealed an apparent limitation to the extent of bone loss. Animals lose bone mass after OVX, but the extent of the bone loss cannot be described as osteoporotic. The small differences between OVX and sham-operated controls in many important bone measurements is overcome by including 15,20 animals per group to provide adequate statistical power. The long-term, at least 16 month, bone safety studies performed to satisfy regulatory guidelines provide an opportunity to study treatment effects for an extended period not covered in shorter-term safety studies. In vivo end-points such as densitometry and biochemical markers translate easily to clinical use, while biomechanical end-points that cannot be measured clinically can be used to predict fracture prevention. To date, the monkey OVX model has been used to support submissions for many new drugs including anabolics, bisphosphonates and selective estrogen receptor modulators. Despite its limitations, the OVX monkey model remains the best characterized of the large animal models of osteopenia and has become integral to osteoporosis drug development. Am. J. Primatol. 71:752,765, 2009. © 2009 Wiley-Liss, Inc. [source]

    Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

    BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2010
    Adam L. VanWert
    Abstract Our understanding of the mechanisms behind inter- and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient- and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender. Copyright © 2009 John Wiley & Sons, Ltd. [source]

    Redefining Affective Disorders: Relevance for Drug Development

    CNS: NEUROSCIENCE AND THERAPEUTICS, Issue 1 2008
    Steven D Targum
    The evaluation of new drug entities with specific modes of action may be hampered by rigid diagnostic classification systems and patient selection processes that do not focus on the anticipated symptomatic, behavioral, and functional outcomes to be achieved. Patients enrolled in central nervous system (CNS) clinical trials may present with a heterogeneous group of symptoms representing several syndromes or subtypes, subsumed under the same diagnosis in the DSM-IV classification system. As a result, enrolled patients may not have the valid illness characteristics of interest to the particular study. We propose that clinical drug development needs to focus on the primary nosological entity likely to be affected by a new drug entity's mode of action. Ideally, a valid patient will have the acute primary symptoms that the novel drug is supposed to influence. In this article, we propose operational criteria to delineate a more symptom-specific and ecologically valid approach to the identification of the valid patient for clinical trials. [source]