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Clinical Trial
, 67 (3), 288-98

A Pharmacokinetic Evaluation of Five H(1) Antagonists After an Oral and Intravenous Microdose to Human Subjects

Affiliations
Clinical Trial

A Pharmacokinetic Evaluation of Five H(1) Antagonists After an Oral and Intravenous Microdose to Human Subjects

Ajay Madan et al. Br J Clin Pharmacol.

Abstract

Aims: 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.

Figures

Figure 1
Figure 1
Chemical structures of diphenhydramine (DPH), NBI-1, NBI-2, NBI-3 and NBI-4. *The position of 14C. One of the two N-CH3 groups was labelled with 14C
Figure 2
Figure 2
Mean concentration–time curves of total 14C and diphenhydramine after a 0.1-mg i.v. and oral dose of diphenhydramine to human volunteers. Each data point is an average of data from four human volunteers. Error bars represent standard deviations. Both 14C and diphenhydramine levels were determined using accelerator mass spectrometry as described in Materials and Methods. IV-0.1 mg (formula image); Oral-0.1 mg (formula image)
Figure 3
Figure 3
Mean concentration–time curves of NBI-1, NBI-2, NBI-3 and NBI-4 after a 0.1-mg i.v. and oral dose of each compound to human volunteers. Each data point is an average of data from four human volunteers. Error bars represent standard deviations. NBI-1, NBI-2, NBI-3 and NBI-4 levels were determined using high-performance liquid chromatography followed by accelerator mass spectrometry as described in Materials and Methods. IV-0.1 mg (formula image); Oral-0.1 mg (formula image)
Figure 4
Figure 4
An assessment of variability in selected pharmacokinetic (PK) parameters after a 0.1-mg i.v. and oral dose of diphenhydramine (DPH), NBI-1, NBI-2, NBI-3 and NBI-4 to human volunteers. PK parameters were calculated from concentration–time curves from each of the four human volunteers as described in Materials and Methods, and are plotted to show the extent of variability observed (see Table 1 for summary data). Oral Cmax, AUC0–t and bioavailability, and CL after i.v. dosing are shown. Horizontal lines are mean data for four subjects

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