臨床薬理

The aim of this study was to evaluate the potential interaction of aprindine and verapamil in the intestinal mucosa. We examined the effects of verapamil on the plasma concentration of aprindine in patients, on the in vitro metabolism of aprindine using cytochrome P450 3A4 human recombinant microsomes and on aprindine metabolism in the gut wall of the beagle dog.
In the clinical studies, verapamil induced a significant increase in the mean plasma concentration of aprindine (p<0.05). The in vitro studies demonstrated that verapamil inhibited metabolism of aprindine through the inhibition of CYP3A4 in a competitive, concentration-dependent manner. In the animal experiments, the administration of verapamil was associated with a 2.2 fold increase in oral bioavailability of aprindine from 33.64 ± 15.22% to 74.05 ± 5.76%. The increased bioavailability could be attributed to an increase of prehepatic bioavailability from 45.53 ± 16.74% to 93.08 ± 9.67% with a minor contribution from increased hepatic bioavailability from 76.00 ± 5.39% to 79.77 ± 3.15%.
These results demonstrate the existence of a route-specific differental effects verapamil on the plasma concentration and oral bioavailability of aprindine. The increased bioavailability and the increased plasma concentration of aprindine is most likely due to the inhibition of gastrointestinal CYP3A4 enzymes. Aprindine is frequently administered in combination with verapamil. Aprindine has a narrow therapeutic range and displays non-linear kinetics, therefore the effects of verapamil on ap.rindine metabolism may be of clinical significance.

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In order to clarify the actual conditions of post marketing surveillance of medicines (PMS), we designed a questionnaire survey and gave it to 235 doctors, nurses, and pharmacists who are staff at Kitasato University Hospital. We took into consideration a smooth and efficient procedure for PMS as well as the means of compliance enforcement, and the security of reliable surveyed data. As a result, the following opinions were obtained:
1) The rate of well-known PMS and good post marketing surveillance practice (GPMSP) of the medical staff tends to lower with the age of doctors (experience fewer than 15 years) and nurses.
2) There were numerous reasons for the acceptance of PMS: “to think about it, it is significant”, “due to policy in the medical office”, “by boss's request”.3) The problem when filling in the questionnaire was that the items on the questionnaire, as well as the clinical test are complicated, and the standard judgement is unknown as well as the timing of judgement.
4) 25% of the doctors filled in the questionnaire after being reminded.
5) The best collaborators to enforce PMS together with doctors were pharmacists, followed by nurses. Another reinforcement was the desire to check on the interactions and adverse reactions of medicines.
6) The awareness of the investigation results of PMS which reflect the medical indications tended to be lower in doctors and nurses, but higher in pharmacists.
7) In order to proceed with PMS smoothly and appropriately, it became clear that the following are necessary: enlightenment of the medical staffs regarding the importance of PMS, the necessity of collaborators, and various improvements and devices to design the questionnaire.

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