In 25 cancer patients treated with slow-release oral morphine (MS Contin^® in 12 patients and Kadian^® in 13 patients) and in 10 cancer patients treated with continuous infusion of morphine, plasma steady-state concentrations of morphine (M), morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) were determined by HPLC. Blood samples were withdrawn at 0 hr, 2 hr, 6 hr after oral administration in patients treated with slow-release oral morphine and once or twice a day in patients treated with continuous infusion of morphine. In 4 cancer patients treated with continuous infusion of morphine, in order to analyze chronopharmacokinetic variability, M-3-G/M ratio was observed at 12: 00 h and 24: 00 h.
No significant changes were observed in M-3-G/M ratios and M-6-G/M ratios at 0, 2, and 6 hr after administration of oral morphine. There was no difference between Kadian^® and MS Contin^®.
The M-3-G/M ratio (38.6±25.7) in the oral morphine group was significantly higher than that (15.3±12.9) of the continuous infusion group (p<0.01). There was approximately a 10-fold interindividual variation in the M-3-G/M ratio in the continuous infusion group and in the oral morphine group.
In conclusion, these results suggest that a large interindividual variation in the metabolism of morphine in oral administration of morphine might be related to variations in the intestinal metabolism of morphine. Further studies are need to clarify this hypothesis.

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An HPLC method for quantifying acetaminophen (APAP) and four of its major metabolites: glucuronide, cysteine, sulfate, and mercapturate conjugates in biologic fluids has been developed. Proteinous samples (25μl) were deproteinized with ZnSO₄-saturated acetonitrile, and urine (100μl) was extracted under alkaline conditions with chloroform-isopropanol (95: 5, v/v) followed by N₂ evaporation. The separations were resolved on a 250mm×4.6mm ID, Phenomenex-ODS reverse-phase column with a simple isocratic mobile phase composed of 0.73 M acetic acid in water (pH 2.44) methanol (90: 10, v/v, plus 15μl/L n-octylamine for serum/plasma; 80: 20, v/v, for saliva and 92: 8, v/v, plus 30μl/L n-octylamine for urine). All compounds were simultaneously detected at a wavelength of 260 nm using the structural analog of APAP, 3-acetamidophenol, as an internal standard. Analysis was achieved within 9 min (for serum/plasma) and 4.5 min (for saliva) or 13.8 min (for urine) per run at a flow rate of 1.5 ml/min. The limits of detection ranged between 6 and 16 ng/ml, while limits of quantitation were 11-103 ng/ml for the compounds. The relationship between peak areas and concentration was linear over the range of 0.088 and 70.00μg/ml for APAP, 0.074 and 14.75μg/ml for APAP cysteine, 0.123 and 197.30μg/ml for APAP glucuronide, 0.205 and 390.21μg/ml for APAP sulfate, and 0.124 and 12.40μg/ml for APAP mercapturate. The resolution chromatograms showed no interfering peaks from endogenous components of biologic fluids. Accuracy of the method ranged from -9.0 to 11.1%, and intra-day and inter-day coefficient of variation ranged from 0.2 to 9.3% and 0.1 to 5.7% for all compounds. Extraction efficiencies of urine samples were between 90.1% and 111.6%. Applicability of the method was examined by a pharmacokinetic study in men and male rats that received one dose of 10 mg/kg of APAP.

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In order to examine the efficient management method of the vast amount of information on adverseevents, a questionnaire survey on the evaluation organization of adverse events in a clinical trial and the implementation of information technology for information management was given to 50 clinical trial sponsors.
Of the sponsors, 64% has a evaluation criteria for the causal relationship of an investigational drug and adverse events, but the 84% is“internal original standard”. With 56% of sponsors, a doctor permanently resides to perform causal relationship evaluation, and 44% of sponsors rely on “outsourcing”. All sponsors with no permanent residence doctor and no evaluation criteria are Japanese companies. A delay in maintenance in information management organization, including the holding frequency of the evaluation committee, was observed in Japanese sponsor.
Among sponsors, 88% replied that it would be useful to create a database of adverse events, presuming that sponsors can correspond with front electric formal data. However, the sponsors do not wish to meet the request from each individual institution, rather they want to offer by standard format; both the sponsor and the institution need to agree on standard data items.

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Immediate post-marketing surveillance (IPMS) is a new safety management system in Japan without parrallel in the rest of the world;the effective enforcement of this system is expected in order to minimize the health hazard caused by critical adverse drug reactions (ADR). However, from the medical institution side, there are some problems which need to be resolved in order to carry out IPMS smoothly . To solve these problems, an experimental investigation using a model medicine was conducted in our institution. At the same time, the research on the status of efforts and activities made by pharmaceutical companies toward IPMS was conducted, followed by problem analysis in implementation of IPMS and a review of the countermeasures.
The main problems found in the new IPMS operation is the lack of cooperation from medical institutions. In order to obtain cooperation from the medical institutions, some incentives are needed, such as, limiting medical institutions for the use of a new developed medicine or design a contract between the pharmaceutical company and medical institution. Two types of contractual coverage are available;one is to provide the prescriber list to medical representative (MR) in written form, and the other is to provide the ADR information collected in the clinical setting by pharmacists in addition to the prescriber list. And, as a contact point of MR visit, the drug information service center may be considered.
Moreover, a model was created based on the contract betweena a pharmaceutical company and medical institution for conducting IPMS effectively and smoothly in the medical institution . This model is characterized by the clear distinction of the pharmacist's role for effective operation of IPMS.

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