Showing papers by "Richard B. Kim published in 2009"

Blood-brain barrier transporters and response to CNS-active drugs.

Abstract: The capillary endothelial cells of the blood−brain barrier express an array of uptake and efflux drug transporters. Regulated expression and function of these transporters govern the central nervous system (CNS) penetration of essential nutrients, therapeutic drugs and, in some cases, toxins. Emerging evidence supports the notion of interplay between uptake and efflux drug transport as the determinants that define the extent of exposure of many drugs and their CNS action. In this brief report, we review a number of key drug transporters known to be expressed at the blood−brain barrier and/or choroid plexus and focus on the implications of such transporters to CNS drug activity, side effects, and toxicity. Specifically, this report focuses on the uptake transporters OATP1A2 (organic anion-transporting polypeptide 1A2) and MCT1 (monocarboxylate transporter 1), which are known to have substrates that are either neuroactive or known to result in CNS side effects and/or toxicity. Furthermore, the efflux transporters P-gp (P-gp; MDR1/ABCB1), BCRP (breast-cancer-resistance protein), OAT3 (organic anion transporter 3), and MRP4 (multidrug-resistance-associated protein 4) are also reviewed. Drug transporters play a fundamental role in protecting the brain from exposure to drugs and other potential toxicants.

Hepatic OATP1B Transporters and Nuclear Receptors PXR and CAR: Interplay, Regulation of Drug Disposition Genes, and Single Nucleotide Polymorphisms

Abstract: Drug uptake transporters are now increasingly recognized as clinically relevant determinants of variable drug responsiveness and unexpected drug-drug interactions. Emerging evidence strongly suggests members of the organic anion transporting polypeptide (OATP) family appear to be particularly important to the disposition of many drugs in clinical use today. Specifically, the liver-enriched OATP1B subfamily members OATP1B1 and OATP1B3 exhibit broad substrate specificity and the ability to transport drugs which are ligands for xenobiotic sensing nuclear receptors such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Accordingly, OATP1B transporters may indirectly regulate expression of drug metabolism genes via modulation of the intracellular concentration of PXR and CAR ligands. Moreover, a number of functionally important single nucleotide polymorphisms (SNPs) in OATP1B transporters have been described. In this review, a brief summary of known SNPs in PXR and CAR will be followed by an in-depth outline of OATP1B1 and OATP1B3 transporters particularly in relation to the known SNPs in these OATPs and the interplay between OATP1B transporters with PXR and CAR, both in vitro and in vivo.

Personalized medicine and antiplatelet therapy: ready for prime time?

Abstract: The concept of personalized medicine is receiving significant attention due to the greater awareness of the influence of genes to the drug effects. Single nucleotide polymorphisms (SNPs) in the DNA are the most frequent form of sequence variations in the human genome and appear to affect the efficacy and safety of many drugs. The term ‘pharmacogenetics’ was coined over 40 years ago with an ultimate goal of using the genetic makeup of an individual to predict drug response and efficacy.1–3 We are just at the beginning of a new era in personalized cardiovascular therapies. However there is little doubt that, in the near future, pharmacogenetic testing will become a valuable tool for a drug and dose selection and thus result in a more desirable benefit/risk ratio for drugs prescribed to patients. Over the past decades, the platelet has emerged as a major pathway involved in cardiovascular diseases. The platelet as a ‘drug target’ has spawned a variety of new drugs that have been shown in large-scale randomized trials to improve patient outcomes in acute coronary syndromes and following percutaneous revascularization procedures.4–6 Until recently aspirin, centred on the tromboxane pathway, was the only antiplatelet agent considered to be the gold standard for effectiveness in both primary and secondary prevention of atherothrombotic diseases.7 Although it continues to be used as the gold standard antiplatelet therapy, adenosine diphosphate (ADP) receptor antagonists and phosphodiesterase inhibitors in combination therapy appear to exert synergistic effects and provide added benefits among high-risk patients for cardiovascular disease.7,8 Nevertheless an important lesson that has emerged from number of trials is that antiplatelet potency per se does not necessarily guarantee enhanced clinical benefit or tolerability for a given patient.8–11 This may in part be due to the … *Corresponding author. Tel: +1 519 663 3553, Fax: +1 519 663 3232, Email: richard.kim{at}lhsc.on.ca

The organic cation transporter, OCTN1, expressed in the human heart, potentiates antagonism of the HERG potassium channel.

Abstract: Background Variable function and expression of drug transporters have been proposed as mechanisms contributing to variable response to drug therapy. Block of the HERG channel, encoding IKr, can lead to serious arrhythmias, and a key drug-blocking site in HERG has been identified on the intracellular face of the pore. We begin to advance the hypothesis that active drug uptake enhances IKr block.

Identification, expression, and functional characterization of full-length and splice variants of murine organic anion transporting polypeptide 1b2.

Abstract: The family of organic anion transporting polypeptides (OATPs) plays an important role in mediating the cellular uptake of numerous endogenous and exogenous compounds. Members of this family include human OATP1B1 and OATP1B3, which have been widely studied and shown to be involved in the hepatic uptake of hormones, bile acids, and many clinically used drugs. However, little is known about the murine orthologue, Oatp1b2. We determined expression of mouse oatp1b2 mRNA and protein using real-time PCR and Western blot analysis. Interestingly, mRNA transcripts and protein were detectable in a number of tissues including kidney and stomach, and, not surprisingly, the highest expression was noted in liver. Cloning of the full coding region of oatp1b2 revealed the presence of two novel splice variants. Interestingly, these splice variants were significantly expressed in organs such as the kidney, but much less in liver. Heterologous expression of the full-length Oatp1b2 cDNA revealed that taurocholic acid, estrone...

Prolonged neutropenia after irinotecan-based chemotherapy in a child with polymorphisms of UGT1A1 and SLCO1B1

Abstract: Genetic polymorphisms of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and SLCO1B1 coding organic anion-transporter polypeptide 1B1, are independent risk factors known to increase irinotecan toxicity in adults. Although combined occurrence of polymorphisms in these 2 genes is likely to influence susceptibility to irinotecan toxicity, data are scarce, especially in children. We report an 11-year-old female with severe and prolonged neutropenia after irinotecan-based chemotherapy. The patient's genotyping revealed polymorphisms in both UGT1A1 and SLCO1B1. To our knowledge, this is the first case report of combined genotyping of both UGT1A1 and SLCO1B1 in a child with severe irinotecan toxicity.

Repetitive Transcranial Magnetic Stimulation (TMS) for medication-resistant depression

Abstract: The FDA has cleared a new device for treatment of major depressive disorder (MDD) resistant to antidepressant medication. The NeuroStar TMS System (Neuronetics) produces pulsed magnetic fields that can induce electrical currents in the brain. Unlike electroconvulsive therapy (ECT), it does not require anesthesia or induction of seizures. Other similar devices are under development.

Introduction to Clinical Pharmacology

Abstract: Publisher Summary The key pathways and mechanisms that determine drug disposition and the pharmacokinetic principles that confer the ability to interpret drug disposition profiles in human subjects are outlined in this chapter. Clinical pharmacology is a discipline dedicated to the bench-to-bedside study of drug action through an in-depth knowledge of human pharmacology and therapeutics. Overall the net effects of the biochemical processes that govern cell membrane permeability and biotransformation determine drug disposition. The application of molecular pharmacology and pharmacogenomics technologies has resulted in important new insights relating to the molecular basis of drug absorption, distribution, metabolism, and excretion. In addition, a fundamental cornerstone of clinical pharmacology is the principles and models that describe drug response in individuals related to drug concentration analysis. The key concepts relating to drug absorption, distribution, metabolism, and excretion (ADME) have been widely accepted and studied in relation to the pharmacokinetics of drug disposition for many decades. For many drugs in clinical use, enzymatic biotransformation to either an inactive metabolite, or in some cases, bioactivation to the therapeutically relevant molecule, has long been noted as the critical step in the overall dispositions of most drugs.

Silodosin (Rapaflo) for benign prostatic hyperplasia

Abstract: Another alpha1a blocker that claims to be more than just another alpha1 blocker.

Dronedarone (Multaq) for atrial fibrillation

Abstract: Dronedarone (Multaq - Sanofi-Aventis) has been approved by the FDA for oral treatment of atrial fibrillation and flutter. Amiodarone (Cordarone, and others) is the most effective drug for this indication, but has considerable toxicity.