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Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteers
Author(s) -
Pageaux G. P.,
Micallef J.,
Nataf M. Barugola,
Levron J. C.,
Lacarelle B.,
Le Moing J. P.,
Bouhours P.,
Blin O.
Publication year - 2001
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2001.01337.x
Subject(s) - dextromethorphan , dextrorphan , pharmacokinetics , medicine , cyp2d6 , hepatic dysfunction , pharmacology , gastroenterology , area under the curve , metabolism , cytochrome p450
Aims The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. Methods The single‐dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX ® capsules). Results The terminal half‐life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 ± 11.5 h; 17.5 ± 10.2 h (mean ± s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 ± 200 ng ml −1 h vs 331 ± 282 ng ml −1 h). There was a significant correlation between the AUC(0,∞) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. Conclusions These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity.