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PHARMACOKINETICS OF MDL 26 479, A NOVEL BENZODIAZEPINE INVERSE AGONIST, IN NORMAL VOLUNTEERS
Author(s) -
ROBBINS DORIS K.,
HUTCHESON SAM J.,
MILLER TERRY D.,
GREEN VICTOR I.,
BHARGAVA VIJAY O.,
WEIR SCOTT J.
Publication year - 1997
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199705)18:4<325::aid-bdd21>3.0.co;2-1
Subject(s) - inverse agonist , pharmacokinetics , benzodiazepine , agonist , pharmacology , medicine , receptor
MDL 26 479 is a new drug undergoing clinical evaluation for the treatment of depression and for memory loss associated with Alzheimer's disease. As part of a dose tolerance trial, the single‐ (SD) and multiple‐dose (MD) pharmacokinetics of MDL 26 479 were evaluated in healthy male volunteers. SDs ranging from 2 to 465 mg, and doses of 30, 60, and 120 mg administered twice daily for 28 d, were examined. Serial blood samples were collected for up to 48 h. Plasma MDL 26 479 concentrations were determined by HPLC. Plasma MDL 26 479 concentration versus time profiles increased rapidly, followed by multiexponential decline. Time to maximum plasma concentration increased over the 230‐fold SD range from 0·5 to 3·8 h. Maximum concentrations and areas under the concentration versus time curves increased disproportionately with dose. Apparent oral clearance estimates decreased from 52·9 to 13·8 L h −1 . MD pharmacokinetic parameters for doses from 30 to 120 mg were consistent with those observed following SD, thus indicating that SD pharmacokinetics are predictive of MD. SD and MD terminal half‐life estimates were similar and independent of dose. ©1997 by John Wiley & Sons, Ltd.