Selecting the optimum dose of theophylline is difficult because of the complication of pharmacokinetics caused by inter-individual variability and the effects of coadministration with other drugs.
The steady-state serum concentration of theophylline (n=221) following repetitive oral administration in 174 hospitalized patients was analyzed using NONMEM. Analysis of the pharmacokinetics of theophylline was accomplished with a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of theophylline were investigated. The clearance of theophylline was significantly influenced by the demographic variables of age, and co-administration with ciprofloxacine or allopurinol. Estimates obtained by NONMEM indicated that the clearance of theophylline in patients under 16 years old was 128% higher than that in those over 16 years old.
Concomitant administration of ciprofloxacine or allopurinol decreased the clearance of theophylline by 56.3% and 69.4%, respectively.
The final regression model of relative clearance of theophylline was: CL (ml/kg/h) =40.5ξ×₅ξ×₆ξ×₇
where ξ₅=0.563 for co-administration of ciprofloxacine, ξ₆=0.694 for co-administration of allopurinol, ξ₇=1.28 for patients younger than 16 years old.
This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent of drug interaction.

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To determine the extent of fetal exposure to cigarette smoking, we measured theconcentrations of nicotine and cotinine in maternal and neonatal hair. In this study of 19 mother-infant pairs, strands of hair were collected from mothers and neonates after birth. These samples were digested by protease, and the nicotine and cotinine concentrations were analyzed by high performance liquid chromatography. In actively smoking mothers, nicotine and cotinine were detected in maternal and neonatal hair. The concentrations of nicotine were 29-398 ng/10 mg of hair in mothers and 11-63 ng/10 mg of hair in neonates. The concentrations of cotinine were 1.7-22.0 ng/10 mg of hair in mothers and 1.6-11.2 ng/10 mg of hair in neonates. In non-smoking mothers with smoking families, nicotine and cotinine were detected in the hair. Hair concentrations of nicotine and cotinine in neonates can be used as a biological marker of the extent of intrauterine exposure to cigarette smoking.

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When carrying out medical examinations, we often encounter the so-called“steeptype plasma glucose subjects”who show a high value of 1-hour postprandial plasmaglucose (1-hr PPG). Therefore, it is considered that there is a possibility of large dispersion of the difference or the change ratio of plasma glucose before and after test medicine is given to subjects in order to carry out a test without the classification of diabetes mellitus for the subjects of diabetes mellitus (DM) or impaired glucose tolerance (IGT) especially in the clinical test of a phase one study. Here, it is considered whether or not subjects are required to be classified by DM, by carrying out 75 g oral glucose tolerance test (OGTT) which is widely acknowledged and applied as the most leading diagnostic method of DM when the clinical study of a cure for DM is carried out.
This particular research included 125 men who were judged to be healthy in the medical examination. Their average age was 32.6±5.1 (mean±SD). As a metabolic function test for plasma glucose, 75 g OGTT was given, and the values of FPG, 1-hr PPG, and 2-hr PPG were measured. Simultaneously, the measurement of HbA_1c was carried out. In terms of the classification of 75 g OGTT (OGTT type), the Japan Diabetes Society (JDS) classified the type based upon“The Classification and Diagnostic Criteria of Diabetes Mellitus”which was revised in May 1999 as follows: JDS classified normal glucose tolerance (NGT-1) into a group of both normal type and a 1-hour value of less than 180 mg/dl. Also, JDS classified NGT-2 into a group of a 1-hour value of more than 180 mg/di after plasma glucose loading in the normal type defined by JDS.
When the proportion of both FPG and OGTT type based upon HbA_1c was examined, 1-hr PPG became 212.6±5.4 (mean±SE) mg/dl in NGT-2 and 203.0±8.0 mg/dl in IGT, respectively. Compared with FPG and 2-hr PPG, no remarkable difference was found between the values of both NGT-2 and IGT in 1-hr PPG. Also, 98 subjects (78.4%) out of all 125 subjects showed both FPG<110 mg/dl and HbA_1c≤5.8%. The details of this particular result are as follows: NGT-1 59 subjects (60.2%), NGT-2 18 subjects (18.4%), IGT 18 subjects (18.4%), and DM 3 subjects (3.1%). Furthermore, 36 subjects aged 20-29 were examined similarly and the results showed NGT-1 18 subjects (50.0%), NGT-2 4 subjects (11.1%), IGT 5 subjects (13.9%), and DM 9 subjects (25.0%).
In conclusion, in the clinical study of a cure for diabetes mellitus, it is important to classify subjects for diabetes mellitus in order to grasp the dispersion of test data more precisely as one of the means. Also, just like IGT, attention must be given to the indication of a high value of 1-hr PPG under the management of a clinical study even if 1-hr PPG is considered to be the normal type in the above diagnostic criteria.

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