The study of codeine-gluthetimide pharmacokinetic interaction in rats.
A high-performance liquid chromatographic (HPLC) assay with native fluorescence detection was developed for the simultaneous quantification of codeine and its two metabolites, morphine and morphine-3-glucuronide (M-3-G), in rat plasma. Solid-phase extraction was used to separate codeine and its metabolites from plasma constituents. Extraction efficiencies of codeine, morphine and M-3-G from rat plasma samples were 97, 92 and 93%, respectively. The chromatographic separation was performed using a reversed-phase C18 column and an elution gradient at ambient temperature. Using native fluorescence detection (excitation at 245 nm and emission at 345 nm), the detection limits of 50 ng/ml for morphine, 25 ng/ml for codeine and 20 ng/ml for M-3-G were obtained. The method had good precision, accuracy and linearity, and was applied to the study of glutethimide's influence on codeine metabolism in rat, following single doses of codeine-glutethimide association. The results confirmed the fact that glutethimide was responsible for a significant increase of morphine plasma levels and for their maintenance in time, concomitant with a significant decrease of M-3-G plasma levels, explained by the inhibition of morphine glucuronidation. In conclusion, glutethimide potentiates and prolongs the analgesic effect of codeine by a pharmacokinetic mechanism.
Popa
Daniela
D
Department of Toxicology, University of Medicine and Pharmacy Iuliu Hatieganu, 13, Emil Isac, 3400 Cluj-Napoca, Romania. dspopa@yahoo.fr
Loghin
Felicia
F
Imre
Silvia
S
Curea
Elena
E
D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003061:Codeine / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D005984:Glutethimide / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D009022:Morphine Derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar
D009022:Morphine Derivatives; D005984:Glutethimide; C018108:morphine-3-glucuronide; D003061:Codeine