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


METHODS
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.


RESULTS
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.


CONCLUSIONS
Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.
Madan
Ajay
A
Neurocrine Biosciences, San Diego, CA 92130, USA. amadan@neurocrine.com
O'Brien
Zhihong
Z
Wen
Jianyun
J
O'Brien
Chris
C
Farber
Robert H
RH
Beaton
Graham
G
Crowe
Paul
P
Oosterhuis
Berend
B
Garner
R Colin
RC
Lappin
Graham
G
Bozigian
Haig P
HP
D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D006634:Histamine H1 Antagonists