IMPACT OF QUINIDINE ON PLASMA AND CEREBROSPINAL-FLUID CONCENTRATIONS OF CODEINE AND MORPHINE AFTER CODEINE INTAKE

Objective: The analgesic effect of codeine depends on its O-demethylat ion to morphine via sparteine oxygenase (CYP2D6) in the liver and pres umably also via this enzyme in the CNS. We studied the ability of quin idine, which is a potent inhibitor of CYP2D6, to penetrate the blood b rain barrier and its possible impact on codeine O-demethylation in CNS . Methods: The study comprised 16 extensive and one poor metaboliser o f sparteine, who underwent spinal anaesthesia for urinary tract surger y or examination. Eight patients were given an oral dose of 125 mg cod eine and 9 patients (including the poor metaboliser) were given 200 mg quinidine 2 h before the same dose of codeine. Plasma and spinal flui d samples were collected 2 h after codeine intake. Results: Free conce ntrations of quinidine were 11-times lower in cerebrospinal fluid than in plasma, and ranged from 9-15 nmol . l(-1). Morphine concentrations were significantly lower in patients pre-treated with quinidine, both in plasma (median 1.45 nmol . l(-1) range 0.74-1.95 nmol . l(-1) vs 9 .86 nmol . l(-1), range 4.59-28.4 nmol . l(-1)) and in cerebrospinal f luid (0.23, 0.16-0.61 nmol . l(-1) vs 3.63, 0.6-8.09 nmol . l(-1)). Th e morphine/codeine concentration ratio in plasma (3.07 x 10(-3), 1.68- 3.68 x 10(-3) vs 19.87 x 10(-3), 9.87-66.22 x 10(-3)) and in cerebrosp inal fluid (0.83 x 10(-3), 0.58-1.45 x 10(-3) vs 2.03-17.7 x 10(-3)) w as also lower. The codeine concentration ratios were significantly low er in cerebrospinal fluid both without and with quinidine, but the dif ference between the plasma and spinal fluid ratios was significantly s maller with quinidine than (p = 0.0002). Conclusion: Quinidine penetra tes the blood brain barrier poorly, but quinidine pre-treatment leads to pronounced lowering of the cerebrospinal fluid concentration of mor phine after codeine intake. However, the O-demethylation of codeine in CNS may not be totally blocked by quinidine.