The change in the serum enzyme activities was studied during a 2-week hospitalization period in 93 healthy young (ages 20 to 29 years) male volunteers.
1) Activities of GOT, GPT, γ-GTP and LAP were significantly elevated during the long-term hospitalization, while LDH and ALP were transiently reduced.
In eight volunteers the GPT level was increased to more than the upper normal value and the γ-GTP level likewise increased in one.
2) The data of subjects who gained over 1 kg during hospitalization resulted in a signifi cant elevation in GOT and a tendency toward GPT elevation.
3) No clear parameter was obtained predicting a change in serum GPT activity from the data prior to the long-term hospitalization. However, the following factors related to the predictive parameters of GPT elevation might be considered:
(1) Obesity before hospitalization is less than 100%.
(2) GOT/GPT ratio is over 3 combined with a low GPT level before hospitalization.
(3) Low level of LAP prior to hospitalization
(4) No weight gain after hospitalization

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The pharmacokinetic properties and antiarrhythmic effects of cibenzoline, a new class I antiarrhythmic drug, were studied in 12 aged patients (mean age 79 years) with frequent ventricular premature contractions (VPC). A single dose of 1.4 mg/kg of cibenzoline was infused intravenously over two minutes. In 3 patients with a creatinine clearance (Ccr) of less than 40ml/min and in 7 patients with Ccr of 40ml/min or higher, the elimination half-life (t_1/2β) was 8.9 hr and 15.4 hr, area under the plasma concentration-time curve (AUC) was 1904ng·hr/ml and 3163 ng·hr/ml, total body clearance (Cl_T) was 217 ml/min and 447 ml/min, and renal clearance (Cl_R) was 86ml/min and 145ml/min, respectively. The t_1/2β AUC, Cl_T and Cl_R showed a close correlation to Ccr. The t_1/2β was prolonged, AUC in-creased, and Cl_T and Cl_R decreased with decreasing renal function.
In 10 out of 12 patients, VPC frequency decreased by more than 90% in 30 minutes after intravenous injection. Therefore, the improvement rate of “markedly or moderately improved” was 83% in the global improvement rating. Side effects observed in 2 patients were as follows: VPC frequency increased in 1 patient and supraventricular premature contraction appeared in 1 patient immediately after intravenous injection. However, these proarrhythmic effects were mild and transient. Cibenzoline significantly prolonged QTc and QRS width. However, cibenzoline showed no effects on R-R and PQ intervals. Though both systolic and diastolic blood pressures were reduced, these reductions were caused by diurnal change.
These results suggest that cibenzoline should be used with caution in elderly patients. In particular, in the presence of renal dysfunction, more careful clinical observation seems man datory, since a significant reduction of elimination was noted.

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The purpose of the present study was to assess the influence of liver diseases on in vitro protein binding. The protein binding of nifedipine and concentrations of albumin, α₁-acid glycoprotein (AAG), HDL-cholesterol (HDL-cho), bilirubin and non-esterified fatty acids (NEFA) were analyzed in sera collected from 6 healthy volunteers, 10 patients with hepatitis and 10 patients with liver cirrhosis. Separation of the unbound fraction was performed by ultracentrifugation at 220, 000g for 18h at 4°C.
The bound fraction (mean ± S. D.) of nifedipine was 98.10 ± 0.91% in normal subjecs, 96.08 ± 1.44% in hepatitis patients (p<0.05) and 94.84 ± 1.60% in cirrhotic patients (p<0.05). The bound fraction was significantly correlated with serum concentrations of AAG (r=0.737, p<0.0001), HDL-cho (r=0.733, p<0.0001), albumin (r=0.5903, p<0.005) and total protein (r=0.459, p<0.05). Multiple regression analysis showed that these varia tions were related to changes in HDL-cho, AAG and NEFA concentrations.

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The effect of dosage form on the pharmacokinetics of cyclosporine (CYA) in steady state after oral administration as either a capsule or a solution was studied in 4 renal trans plant recipients.
CYA (dose; 100-350mg/day) was administered orally to the patients (17-49 years old) every 12 hr. The whole blood levels were measured by fluorescence polarization immu noassay (FPIA) based on monoclonal antibody. The blood specimens were collected just before administration (0h) in the morning and at1 (1h), 2 (2h), (3h), 6 (6h), 8 (8h) hours after administration; specimens were also collected just before the evening administration (12h) and at1 (13h), 2 (14h), 3 (15h), 4 (16h), 7 (19h), 12 (24h) hours after administration in one day.
There were no significant differences between capsule and solution the administrations in the area-under-the-curve (AUC), and in the maximal blood concentration (C_max). There was a significant difference between the trough level of 0h and 24h, and between the time of maximum blood concentration (T_max) after the administration of solution in the daytime and that at nighttime (p<0.05).
These results suggest that the capsule is not only as applicable as solution in changeover patients but also very useful for trough blood level monitoring.

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The influence of agihg an the hepatic metabolism of propranolol, i. e. conjuation, sidechain oxidaion and ring fxidation, was investigated in 32 inpatients aged 30 to 84 yr. Plasma propranolol concentaion and urinary main metabolites [propranolol glucuronide (PPLG), naphthoxylactic acid (NLA), and 4-hydroxypropranolol (4OHP) were measured after a single oral dose of 20mg propranolol. There were significant correlations between age and
1) maximum propranolol concentration, 2) area unde the plasma concentration-time curve and 3) elimination half-life. Apparent oral clearance of propranolol was invesely correlated with age. Partial metabolic clearance (PMC) to 4OHP (ring oxidation) and PMC to NLA (side-chain oxidation) were significantly correlaed with age, while PMC to PPLG was not. In addition, the ratio of PMC to 4OHP to that of PMC to NLA was mot associated with age. These obserations suggest that there are age-related reductions in two oxidizing capacities, while there is no significant infuence of aging on the conugating capacity. The age-related reduction in oral clearance of propranolol may be Rainly caused by the decline in the capacity of two diffrent oxidation pathways.

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In order to investigate the utility of therapeutic monitoring of mexiletine aided by the saliva drug levels, serum (total and unbound fraction) and saliva drug concentrations were measured in six inpatients with ventricular arrhythmia who were given an oral daily dose of 150 or 300 mg (t. i. d.) of mexiletine hydrochloride.
Mexiletine levels in saliva were consistently much higher than the levels in serum of the patients. Saliva level to total and unbound serum drug concentration ratio (S/S ratio) varied markedly among patients from 4.5 to 32.0 and from 9.6 to 68.6, respectively, on the first day of medication. The predicted levels of mexiletine in the serum on day 7 and day 14 using the mean S/S ratio obtained on the first day of medication were almost identical to the observed levels in three of these patients, who showed a small ratio of saliva to total serum concentration, less than about 9 (or 21 for the ratio to unbound concentration). There was no correlation between the mexiletine level in saliva and the salivary flow rate.
Four patients who received the drug at a daily dose of 300mg showed almost favorable trough drug levels in the serum total fraction ranging from 0.164 to 0.583 μg/ml, and ventricular premature contraction (VPC) in these patients was almost completely reduced (94.7-100.0%), except for one non-responder. Two patients who received 150 mg of the drug showed steady-state trough levels in the serum total fraction of less than 0.1μg/ml and the VPC of one of these two patients was hardly controlled. We, therefore, increased the daily dose to 300 mg in this patient, who was well controlled thereafter.
From these findings, it is suggested that it may be possible to estimate the serum mexiletine levels from the saliva drug levels by using the initial S/S ratios inpatients with ratios of less than about 9.

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