Absorption, Distribution, Metabolism, and Excretion

The Journal of

PHARMACOLOGY

And Experimental Therapeutics

A Publication of the American Society for Pharmacology and Experimental Therapeutics

September 2003

Vol. 306, No. 3

ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Contribution of Lymphatically Transported TestosteroneDavid M. Shackleford,

Undecanoate to the Systemic Exposure of Testosterone afterW. A. (Fried) Faassen, Natalie Houwing,

Oral Administration of Two Andriol Formulations inHolger Lass, Glenn A. Edwards,

Conscious Lymph Duct-Cannulated DogsChristopher J. H. Porter, and

William N. Charman

Contents

PERSPECTIVES IN PHARMACOLOGY

The Cholinergic Hypothesis of Age and Alzheimer's Disease-Related Cognitive Deficits: Recent Challenges and Their Implications for Novel Drug Development

Characterization of Blood-Brain Barrier Permeability to ,* in the Mouse

Avasimibe Induces CYP3A4 and Multiple Drug Resistance Protein 1 Gene Expression through Activation of the Pregnane X Receptor

Multiple Injections of Pegylated Liposomal Doxorubicin: Pharmacokinetics and Therapeutic Activity

Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta

Genetic Variability at the Human FMO1 Locus: Significance of a Basal Promoter Yin Yang 1 Element Polymorphism

(FMO 1*6)

A. V. Terry Jr. and J. J. Buccafusco

Naoko Nonaka, Seiji Shioda,

Michael L. Niehoff, and William A. Banks

Jasminder Sahi, Mark A. Milad, Xianxian Zheng, Kelly A. Rose, Hongbing Wang, Linda Stilgenbauer, Darryl Gilbert, Summer Jolley, Ralph H. Stern, and Edward L. LeCluyse

Gregory J. R. Charrois and Theresa M. Allen

Sujal V. Deshmukh, Tatiana N. Nanovskaya, and Mahmoud S. Ahmed

Ronald N. Hines, Zhaohui Luo, Kathleen A. Hopp, Erwin T. Cabacungan, Sevasti B. Koukouritaki, and D. Gail McCarver

821

925

948 1027

1058 1099

1210

BEHAVIORAL PHARMACOLOGY

Topical Capsaicin-Induced Allodynia in Unanesthetized Primates: Pharmacological Modulation

Temporal Effects of Stress by Immobilization and Sensitivity of the Isolated Rat Pacemaker to Isoproterenol: Roles of Corticosterone, Neuronal Uptake, and /3-Adrenergic Homogeneity

GABAergic Systems Modulate Nicotinic Receptor-Mediated Seizures in Mice

Relative Efficacy of Buprenorphine, Nalbuphine and Morphine in Opioid-Treated Rhesus Monkeys Discriminating

Naltrexone

CARDIOVASCULAR

Role of Peripheral Benzodiazepine Receptors in Mitochondrial, Cellular, and Cardiac Damage Induced by Oxidative Stress and Ischemia-Reperfusion

Nicotine Induces a Long QT Phenotype in Kcnql-Deficient

Mouse Hearts

Effects of Reboxetine on Sympathetic Neuroeffector Transmission in Rabbit Carotid Artery

Eduardo R. Butelman, Jonathan W. Ball,1106

Todd J. Harris, and Mary Jeanne Kreek

Marco Aurelio de Paula Brotto1152

Peter Dobelis, Scott Hutton, Ying Lu, and1159

Allan C. Collins

Stacy L. Sell, Lance R. McMahon, and1167

Charles P. France

Nathalie Leducq, Francoise Bono,828

Thierry Sulpice, Valerie Vin, Philip Janiak, Gerard Le Fur, Steve E. O'Connor, and Jean-Marc Herbert

Toshimasa Tosaka, Mathew C. Casimiro,980

Qi Rong, Srihari Telia, Michelle Oh, Alexander N. Katchman, John C. Pezzullo, Karl Pfeifer, and Steven N. Ebert

Lasse E. Rasmusscn and Ove A. Nedergaard995

Pilot Intervention: Aerosolized AdrenomeduIIin Reduces Pulmonary Hypertension

Inhibition of Canine (NCX1.1) and Drosophita (CALX1.1) Na+-Ca2+ Exchangers by 7-Chloro-3,5-dihydro-5-phenyl-lff-4,1 -benzothiazepine-2-one (CGP-37157)

Pharmacological Interruption of Acute Thrombus Formation with Minimal Hemorrhagic Complications by a Small Molecule Tissue Factor/Factor Vila Inhibitor: Comparison to Factor Xa and Thrombin Inhibition in a Nonhuman Primate Thrombosis Model

Pharmacological Characterization of the New Stable Antiarrhythmic Peptide Analog Ac-D-Tyr-D-Pro-D-Hyp-Gly-D-Ala-Gly-NH2 (ZP123): In Vivo and in Vitro Studies

Functional and Binding Characterizations of Urotensin II-Related Peptides in Human and Rat Urotensin II-Receptor Assay

Michael A. Kandler, Katharina von der Hardt, Suleiman Mahfoud, Martin Chada, Ellen Sclioof, Thomas Papadopouios, Wolfgang Rascher, and Jorg Dotsch

Alexander Omelchenko, Ron Bouchard, Hoa Dinh Le, Platon Choptiany, Neeraj Visen, Mark Hnatowich, and Larry V. Hryshko

Osman D. Suleymanov, James A. Szalony, Anita K. Salyers, Rhonda M. LaChance, John J. Parlow, Michael S. South, Rhonda S. Wood, and Nancy S. Nicholson

Anne Louise Kj0lbye,

Carsten Boye Knudsen, Trine Jepsen,

Bjarne Due Larsen, and

J0rgen S0berg Petersen

Alexandre Brkovic, Almut Hattenberger, Evi Kostenis, Thomas Klabunde, Stefanie Flohr, Michael Kurz, Steve Bourgault, and Alain Fournier

1021

1050

1115

1191

1200

CELLULAR AND MOLECULAR

A Selective and Oral Small Molecule Inhibitor of Vascular Epithelial Growth Factor Receptor (VEGFR)-2 and VEGFR-1 Inhibits Neovascularization and Vascular Permeability

Dopamine Modulation of Membrane Excitability in Striatal Spiny Neurons is Altered in DARPP-32 Knockout Mice

The Cytoplasmic Domain of Alzheimer's Amyloid-j3 Protein Precursor Causes Sustained Apoptosis Signal-Regulating Kinase 1/c-Jun NH2-Terminal Kinase-Mediated Neurotoxic

Signal via Dimerization

cDNA Microarray Analysis Reveals a Nuclear Factor-KB-Independent Regulation of Macrophage Function by Adenosine

Cilostazol Prevents Tumor Necrosis Factor-a-Induced Cell Death by Suppression of Phosphatase and Tensin Homolog Deleted from Chromosome 10 Phosphorylation and Activation of Akt/Cyclic AMP Response Element-Binding Protein

Phosphorylation

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of Peroxisome Proliferator-Activated Receptor-y, Pioglitazone

Reversal of Multiple Drug Resistance in Cholangiocarcinoma by the Glutathione S-Transferase-Tr-Specific Inhibitor Ol-Hexadecyl-y-glutamyl-S-benzylcysteinyl-D-phenylglycine Ethylester

Neela Patel, Li Sun, Deborah Moshinsky, Hui Chen, Kathleen M. Leahy, Phuong Le, Katherine G. Moss, Xueyan Wang, Audie Rice, Danny Tarn, A. Douglas Laird, Xiaoming Yu, Qingling Zhang, Cho Tang, Gerald McMahon, and Anthony Howlett

Shao-Pii Onn, Allen A. Fienberg, and Anthony A. Grace

Yuichi Hashimoto, Takako Niikura, Tomohiro Chiba, Emi Tsukamoto, Hisae Kadowaki, Hideki Nishitoh, Yohichi Yamagishi, Miho Ishizaka, Marina Yamada, Mikiro Nawa, Kenzo Terashita, Sadakazu Aiso, Hidenori Ichijo, and Ikuo Nishimoto

Zoltan H. Nemeth, S. Joseph Leibovich, Edwin A. Deitch, E. Sylvester Vizi, Csaba Szabd, and Gyorgy Hasko

Ki Whan Hong, Ki Young Kim, Hwa Kyoung Shin, Jeong Hyun Lee, Jae Moon Choi, Yong-Geun Kwak, Chi Dae Kim, Won Suk Lee, and Byung Yong Rhim

Nobuyuki Enomoto, Yoshiyuki Takei, Miyoko Hirose, Akira Konno, Tomoyoshi Shibuya, Shujiro Matsuyama, Satoko Suzuki,

Kenichi Ikejima Tsuneo Kitamura, and Nobuhiro Sato

Takaharu Nakajima, Tetsuji Takayama, Koji Miyanishi, Atsushi Nobuoka, Tsuyoshi Hayashi, Tomoyuki Abe, Junji Kato, Kiyoyuki Sakon, Yoshimitsu Naniwa, Hirohumi Tanabe, and Yoshiro Niitsu

838

870 889

1042

1182

846

861

INFLAMMATION AND IMMUNOPHARMACOLOGY

A Small Molecule ct4fotlfx4$7Antagonist Differentiates between the Low-Affinity States of a^ and a4f57: Characterization of Divalent Cation Dependence

Evidence for Cannahinoid Receptor-Dependent and -Independent Mechanisms of Action in Leukocytes

Effect of Ibuprofen on Neutrophil Migration in Vivo in Cystic Fibrosis and Healthy Subjects

The Orally Available Spleen Tyrosine Kinase Inhibitor 2-[7-(3,4-Dimethoxy phenyl)-imidazo[l,2-c]pyrimidin-5-ylamino]-nicotinamide Dihydrochloride (BAY 61-3606) Blocks Antigen-Induced Airway Inflammation in Rodents

Linda A. Egger, Jin Cao, Christine McCallura, Usha Kidambi, Gail Van Riper, Ermengilda McCauley, Richard A. Mumford, Thomas J. Lanza, Linus S. Lin, Stephen E. de Laszlo, David N. Young, Ginger Yang, Dennis C. Dean, Conrad E. Raab, Mike A. Wallace, Allen N. Jones, William K. Hagmann, John A. Schmidt, R. Blake Pepinsky, Daniel M. Scott, Wen-Cherng Lee, Mark A. Cornebise, and Patricia A. Detmers

Barbara L. Faubert Kaplan, Cheryl E. Rockwell, and Norbert E. Kaminski

Michael W. Konstan, Jeanne E. Krenicky, Marcie R. Finney, H. Lester Kirchner, Kathleen A. Hilliard, Jay B. Hilliard, Pamela B. Davis, and Charles L. Hoppel

Noriyuki Yarnamoto, Keisuke Takeshita, Mkhitaka Shichijo, Toshio Kokubo, Masako Sato, Kosuke Nakashima, Mina Ishimori, Hiroichi Nagai, Ying-Fu Li, Takeshi Yura, and Kevin B. Bacon

903

1077

1086

1174

NEUROPHARMACOLOGY

Sympathetic Innervation in the 1 -Methyl -4-phenyl-l,2,3,6-tetrahydropyridine Primate Model of Parkinson's Disease

Differential Regulation of the Endocannabinoids Anandamidc and 2-Arachidonylglycerol within the Limbic Forebrain by Dopamine Receptor Activity

Differential Actions of Fipronil and Dieldrin Insecticides on GABA-Gated Chloride Channels in Cockroach Neurons

Steroids Modulate /V-Methyl-D-aspartate-stimulated [3H]Dopamine Release from Rat Striatum via or Receptors

The Novel Melatonin Agonist Agomelatine (S20098) Is an Antagonist at 5-Hydroxytryptamine2c Receptors, Blockade of Which Enhances the Activity of Frontocortical Dopaminergic and Adrenergic Pathways

jx-Opioid-Induced Desensitization of Opioid Receptor-Like 1 and fi-Opioid Receptors: Differential Intracellular Signaling * Determines Receptor Sensitivity

L-Setegiline Potentiates the Cellular Poly(ADP-Ribosyl)ation Response to Ionizing Radiation

The Endogenous Cannabinoid Anandamide Inhibits a? Nicotinic Acetylcholine Receptor-Mediated Responses in

Xenopus Oocytes

/V-H-Alkylpyridinium Analogs, a Novel Class of Nicotinic Receptor Antagonists: Selective Inhibition of Nicotine-Evoked [3H]Dopamine Overflow from Superfused Rat Striatal Slices

Effect of Transport Inhibitors and Additional Anti-HIV Drugs on the Movement of Lamivudine (3TC) across the Guinea Pig Brain Barriers

Group II Metabotropic and a-Amino-3-hydroxy-5-methyl-4-isoxazole Propionate (AMPA)/Kainate Glutamate Receptors Regulate the Deficit in Brain Reward Function Associated with Nicotine Withdrawal in Rats

Treatment of Adverse Effects of Excessive Phencyclidine Exposure in Rats with a Minimal Dose of Monoclonal Antibody

Role of Na+,K+-ATPase in Morphine-Induced Antinociception

David S. Goldstein, Sheng-Ting Li, Courtney Holmes, and Krys Bankiewicz

Sachin Patel, David J. Rademacher, and Cecilia J. Hillard

Xilong Zhao, Vincent L. Salgado, Jay Z. Yeh, and Toshio Narahashi

Samer J. Nuwayhid and Linda L. Werling

M. J. Millan, A. Gobert, F. Lejeune, A. Dekeyne, A. Newman-Tancredi, V. Pasteau, J.-M. Rivet, and D. Cussac

Chitra D. Mandyam, Deepak R. Thakker, and Kelly M. Standifer

Christine Brabeck, Ragen Pfeiffer,

Alan Leake, Sascha Beneke, Ralph Meyer,

and Alexander Biirkle

Murat Oz, Arippa Ravindran, Oscar Diaz-Ruiz, Li Zhang, and Marisela Morales

Vladimir P. Grinevich, Peter A. Crooks, Sangeetha P. Sumilhran, Aaron J. Haubner, Joshua T. Ayers, and Linda P. Dwoskin

J. E. Gibbs, T. Rashid, and S. A. Thomas

Paul J. Kenny, Fabrizio Gasparini, and Athina Markou

Elizabeth M. Laurenzana,

Melinda G. Gunnell, W. Brooks Gentry, and

S. Michael Owens

Willias Masocha, Gyongyi Horvath, Ahmad Agil, Maria Ocafia, Esperanza Del Pozo, Margit Szikszay, and Jose M. Baeyens

855 880

914 934 954

965

973

1003

1011

ATP Augments Peptide Release from Rat Sensory Neurons in Culture through Activation of P2Y Receptors

Long-Term Effects of Olanzapine, Risperidone, and Quetiapine on Ionotropic Glutamate Receptor Types: Implications for Antipsychotic Drug Treatment

TOXICOLOGY

Rat Hepatic CYP2E1 Is Induced by Very Low Nicotine Doses: An Investigation of Induction, Time Course, Dose Response, and Mechanism

Role of Cysteine S-Conjugate 0-Lyase in the Metabolism of Cisplatin

Comparative Effects of Methylmercury and Hg2+ on Human Neuronal N- and R-Type High-Voltage Activated Calcium Channels Transiently Expressed in Human Embryonic Kidney

293 Cells

H. Huang, X. Wu, G. D. Nicol, S. Meller, and M. R. Vasko

Frank I. Tarazi, Ross J. Baldessarini, Nora S. Kula, and Kehong Zhang

Alina L. Micu, Sharon Miksys,

Edward M. Sellers, Dennis R. Koop, and

Rachel F. Tyndale

Lei Zhang and Marie H. Hanigan

Ravindra K. Hajela, Shuang-Qing Peng, and William D. Atchison

1145

941

988 1129