A pharmacokinetic evaluation of five H(1) antagonists after an oral and intravenous microdose to human subjects

• Published in: British journal of clinical pharmacology 2009-03, Vol.67 (3), p.288
• Main Authors: Madan, Ajay, O'Brien, Zhihong, Wen, Jianyun, O'Brien, Chris, Farber, Robert H, Beaton, Graham, Crowe, Paul, Oosterhuis, Berend, Garner, R Colin, Lappin, Graham, Bozigian, Haig P
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Chromatography, High Pressure Liquid; Cross-Over Studies; Dose-Response Relationship, Drug; Histamine H1 Antagonists - administration & dosage; Histamine H1 Antagonists - pharmacokinetics; Humans; Injections, Intravenous; Male; Middle Aged; Young Adult
• ISSN: 1365-2125
• DOI: 10.1111/j.1365-2125.2008.03351.x

To evaluate the pharmacokinetics (PK) of five H(1) receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). Five H(1) 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. The median clearance (CL), apparent volume of distribution (V(d)) and apparent terminal elimination half-life (t(1/2)) of diphenhydramine after an i.v. microdose were 24.7 l h(-1), 302 l and 9.3 h, and the oral C(max) and AUC(0-infinity) 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. Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.