A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects

Madan, Ajay, O'Brien, Zhihong, Wen, Jianyun , O'Brien, Chris, Farber, Robert H., Beaton, Graham, Crowe, Paul, Oosterhuis, Berend, Garner, R. Colin, Lappin, Graham and Bozigian, Haig P. (2009) A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects. British Journal of Clinical Pharmacology, 67 (3). pp. 288-298. ISSN 0306-5251

Full content URL: http://dx.doi.org/10.1111/j.1365-2125.2008.03351.x

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Item Type:Article
Item Status:Live Archive

Abstract

AIMS: To evaluate the pharmacokinetics (PK) of five H1 receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). METHODS: Five H1 receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. RESULTS: The median clearance (CL), apparent volume of distribution (V d) and apparent terminal elimination half-life (t1/2) of diphenhydramine after an i.v. microdose were 24.7 l h-1, 302 l and 9.3 h, and the oral Cmax and AUC0-� were 0.195 ng ml-1 and 1.52 ng h ml-1, respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. CONCLUSIONS: Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection. © 2009 Neurocrine Biosciences.

Keywords:diphenhydramine, histamine H1 receptor antagonist, nbi 1, nbi 2, nbi 3, nbi 4, unclassified drug, adult, animal experiment, area under the curve, article, clinical trial, controlled clinical trial, controlled study, crossover procedure, dog, drug bioavailability, drug blood level, drug clearance, drug distribution, drug dose, drug half life, human, human experiment, male, maximum plasma concentration, microdose, monkey, nonhuman, normal human, priority journal, quantitative assay, randomized controlled trial, rat, single drug dose, time to maximum plasma concentration, Administration, Oral, Adult, Chromatography, High Pressure Liquid, Cross-Over Studies, Dose-Response Relationship, Drug, Histamine H1 Antagonists, Humans, Injections, Intravenous, Middle Aged, Young Adult
Divisions:College of Science > School of Pharmacy
ID Code:8221
Deposited On:24 Mar 2013 16:45

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