Objective: The analgesic effect of codeine depends on its O-demethylation to morphine via sparteine oxygenase (CYP2D6) in the liver and presumably also via this enzyme in the CNS. We studied the ability of quinidine, which is a potent inhibitor of CYP2D6, to penetrate the blood brain barrier and its possible impact on codeine O-demethylation in CNS.
Methods: The study comprised 16 extensive and one poor metaboliser of sparteine, who underwent spinal anaesthesia for urinary tract surgery or examination. Eight patients were given an oral dose of 125 mg codeine and 9 patients (including the poor metaboliser) were given 200 mg quinidine 2 h before the same dose of codeine. Plasma and spinal fluid samples were collected 2 h after codeine intake.
Results: Free concentrations 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 fluid (0.23, 0.16-0.61 nmol.l-1 vs 3.63, 0.6-8.09 nmol.l-1). The 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 cerebrospinal fluid (0.83 d 10 (-3), 0.58-1.45 x 10 (-3) vs 7.19 x 10 (-3), 2.03-17.7 x 10 (-3) was also lower. The morphine/codeine concentration ratios were significantly lower in cerebrospinal fluid both without and with quinidine, but the difference between the plasma and spinal fluid ratio was significantly smaller with quinidine than without (p = 0.0002).
Conclusion: Quinidine penetrates the blood brain barrier poorly, but quinidine pre-treatment leads to pronounced lowering of the cerebrospinal fluid concentration of morphine after codeine intake. However, the O-demethylation of codeine in CNS may not be totally blocked by quinidine.