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CYP3A5 but Not CYP2D6 Polymorphism Contributes Significantly to the Variability in Dextropropoxyphene Disposition
Author(s) -
Yin Ophelia Q. P.,
Tomlinson Brian,
Chow Moses S. S.
Publication year - 2010
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009359006
Subject(s) - propoxyphene , pharmacokinetics , cyp2d6 , pharmacology , chemistry , cyp2c9 , medicine , genotype , analgesic , biochemistry , gene
This study evaluated the effect of CYP2D6, CYP3A4, and CYP3A5 polymorphisms on dextropropoxyphene disposition in healthy subjects. A total of 14 healthy male Chinese subjects received a single oral dose of a combination tablet of 325 mg of paracetamol and 32.5 mg of dextropropoxyphene. Serial blood samples were collected for up to 24 hours to determine plasma concentrations of paracetamol, dextropropoxyphene, and nordextropropoxyphene by liquid chromatography—tandem mass spectroscopy. CYP2D6, CYP3A4, and CYP3A5 genotyping were performed using polymerase chain reaction—based methods. No CYP3A4 mutant alleles were detected in the study subjects. There were no significant differences (P > .05) in dextropropoxyphene and nordextropropoxyphene pharmacokinetics among CYP2D6 genotypes. In contrast, plasma concentrations of dextropropoxyphene were significantly higher (peak plasma concentration, 54.4 ± 25.5 vs 31.0 ± 10.9 ng/mL; area under the plasma concentration‐time curve, 260.8 ± 88.1 vs 142.3 ± 42.4 ng·h/mL, both P < .05) and apparent oral clearance value was significantly lower (2.2 ± 0.9 vs 3.6 ± 1.4 L/h/kg, P < .05) in CYP3A5*3/*3 (n = 8) than CYP3A5*1/*3 (n = 5) subjects. Nordextropropoxyphene exposure also tended to be higher in CYP3A5*3/*3 subjects, but the difference was not statistically significant between the 2 groups. One subject who was identified as a CYP3A5*1/*1 carrier exhibited a very high apparent oral clearance value of 12.5 L/h/kg. No significant difference in paracetamol pharmacokinetics was observed among CYP2D6 or CYP3A5 genotypes. These results suggest that CYP3A5 but not CYP2D6 polymorphisms appear to exert a significant influence on dextropropoxyphene disposition.