PHARMACOKINETICS AND DRUG INPUT CHARACTERISTICS FOR A DICLOFENAC-CODEINE PHOSPHATE COMBINATION FOLLOWING ORAL AND RECTAL ADMINISTRATION

In a single dose cross-over study with 12 healthy male volunteers the plasma concentrations of diclofenac (CAS 15307-86-5) and codeine (CAS 76-57-3) were determined after oral and rectal application of formulat ions containing 50 mg of each drug. For kinetic analysis of the concen tration-time profiles non-compartmental as well as compartmental proce dures were used. The compartment model included two disposition compar tments supplemented by a dissolution and drug absorption step. For bot h compounds, the AUC(0-infinity) values of the two treatments were sim ilar with only a slightly higher AUC for the suppositories, which was not found to be significantly different under the employed conditions (p > 0.05). Referring to the pharmacokinetic parameters C-max and t(ma x) typical differences between oral and rectal formulations were obser ved. For the suppositories, diclofenac and codeine average peak plasma concentrations were only half as high as for the tablets, whereas the respective t(max) values were doubled. The results obtained show a si milar extent of diclofenac and codeine bioavailability for both admini stration routes, but the rate of drug input was lower for the supposit ories. The total mean input time (MIT(tot)) was found to be significan tly longer for the suppositories. This seems to be caused by a slow re lease from the dosage form or dissolution of the drugs, which is confi rmed by a longer MIT(tot) compared to the MRT(sys) in most of the volu nteers.