It is well known that change in drug distribution occur in association with hepatic disease. The prediction of the variation in the volume of distribution of drugs at steady-state (Vd_ss) in hepatic disease is very useful for the planning of drug dosage regimens.
In the present study, we tried to develop methodology for estimating Vd_ss in hepatic disease based on physiological pharmacokinetics. The following two methods were utilized to predict Vd_ss in hepatic disease (hepatic cirrhosis and hapatitis). Method 1 : Vd_ss in hepatic disease was predicted assuming that Vd_ss in hepatic disease is not different from that in the normal condition. Method 2 : it is assumed that hepatic disease could not lead to alterations in the tissue binding but in the plasma binding, Vd_ss in hepatic disease was calculated according to the mass balance equation (Vd_ss=7.2+7.8·f_P+27·fp/f_T ; where f_P and f_T are plasma and tissue unbound fraction, respectively) by using the data of Vd_ss and fp in normal condition and that in hepatic disease. In hapatic cirrhosis, a significant correlation between the observed and predicted values according to Method 1 was obtained with a slope of regression line of 0.79 (p<0.001). On the other hand, a significant linear correlation between the observed and predicted values according to Method 2 was obtained with a slope of 1.03 (p<0.001). Furthermore, a significant difference in percent errors between the two methods was observed (p<0.05). In hepatitis, same resuls were also obtained.
In conclusion, it is suggested that the extent of intrinsic tissue binding of various drugs is little altered in hepatic disease. The prediction of the apparent volume of distribution in hepatic disease according to Method 2 was successful for most drugs studied and very useful for clinical use.

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The risk of adverse reaction on the central nervous system induced by H₂ receptor antagonists were pharmacokinetically/pharmacodynamically evaluated. The toxic concentration of H₂ receptor antagonists, such as cimetidine (CIM), ranitidine(RAN) and famotidine(FAM) in the cerebrospinal fluid (CSF) and plasma, and the H₂ receptor occupancies were predicted from the dissociation constants from H₂ receptor in the brain and the CSF/plasma concentration ratios of these drugs. Furthermore, change of CSF/plasma concentration ratio of RAN and FAM in patients with renal or hepatic disease was estimated from the data of CIM. The estimated toxic dose of H₂ receptor antagonists in these disease states, especially in hepatic disease, is very close to the usual dose. Therefore, RAN and FAM may also have an ability to induce an adverse reaction on the central nervous system in the case of renal or hepatic disease.

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Eptastigmine, ((3aS, 8aR)-1, 2, 3, 3a, 8, 8a-hexahydro-1, 3a, 8-trimethylpyrrolo [2, 3-b] indol-5-ol-heptylcarbamate L-tartrate), is a competitive inhibitor of acetylcholinesterase. Absorption, distribution and excretion of radioactivity were investigated in rats (n=3) after single oral or intravenous administration of ³H-eptastigmine.
1. After oral administration of doses ranging from 2 to 8mg/kg, blood levels of radioactivity increased proportionally to administered dose with peak blood concentration occurring at about one hour and declined with half-lives (t_1/2β) of 13-16hr. Based on the AUC values obtained after intravenous and oral administration, oral absorption ratio of ³H-eptastigmine was estimated to be 70-100%.
2. After oral dosin g, the radioactivity was rapidly and widely distributed to tissues and maintained in high concentrations in the liver and gastrointestinal tract. Radioactivity in most of tissues declined slower than that in the plasma. At 24hr, the level in each tissue decreased to about 10% of the corresponding maximum level. There was no evidence of accumulation of ³H in any tissue.
3. Mean excretion of radioactivity was 60.5 and 18.1% of the dose in the urine and feces, respectively, within 24hr after intravenous dosing. In case of oral dosing, the mean excretion of radioactivity in urine and feces were 40.2-51.3 and 29.0-33.5% of the dose, respectively.
4. Mean plasma levels of unchanged eptastigmine reached the maximum concentration at 0.5hr after oral dosing, and then declined with half-life of 1.1hr. The AUC value for unchanged eptastigmine accounted only for 0.4% of that for the total radioactivity.
5. Marked inhibition of RBC acetylcholinesterase activity was o bserved after administration of the 8mg/kg. At 1hr after dosing, the mean value of acetylcholinesterase activity decreased to 15% of the pre-dosing level and remained suppressed for up to 8hr after dosing.
6. Based on the results from the blood profile of radioactivity and time course of acetylcholinesterase inhibition, we concluded that at least one active metabolite exists in the blood.

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The plasma concentration, distrib ution and metabolism of [¹⁴C]miconazole ([¹⁴C])MCZ) were studied after application of [¹⁴C]MCZ gel (10mg/kg of miconazole) to oral mucosa of male rats.
1. After application, the plasma radioactivity reached the maximum level of 1.82μg eq./ml at 2hr, and then declined in a similar manner as after oral administration of [¹⁴C]MCZ.
2. At 1hr after application, high levels of radioactivity were observed in the epidermis of lip, palatum, tongue and buccal mucosa on the enlarged autoradiograms, and the radioactivity was high in the epidermis of buccal mucosa, while low in the buccal muscle.
3. At 1 and/or 6hr after application, the unchanged drug was the main component of radioactivity in the buccal muscle and epidermis of the buccal mucosa, and the minor quantities of other compounds were also detected in each tissue ; oxidative ring-broken form (M8) in both tissues, and Uk3 and Uk10, unknown metabolites in the buccal muscle.

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Metabolic fate of a high molecular-weight s odium hyaluronate (SL-1010), a highly purified preparation from the culture medium of Streptococcus zooepidemicus, was studied in rabbits after intraarticular injection into the knee.
1. Radioactivity in the synovial fluid was eliminated biphasically with apparent half-life of 32hr during the first phase, when most radioactivity was eliminated. Gel filtration patterns showed that the SL-1010, a low molecular-weight fraction, was eliminated from the joint cavity faster than the high molecular-weight fraction.
2. In joint region, higher radioactivity was detected in the synovial tissue, and much less radioactivity was observed in the articular cartilage, meniscus and ligament. Total radioactivity in the rest of the whole body was less than that in the knee joint. The highest levels were in Harder's gland, and followed by reticuloendothelial tissues, such as the liver and spleen. Radioactivity was much lower in other tissues including plasma, and there was no radioactivity in the sodium hyaluronate (HA) fraction isolated from liver and plasma. Gel filtraton patterns showed that the main molecular-weight distribution of HA isolated from synovial tissue 24, 48 and 72hr after injection was similar to that of ¹⁴C-SL-1010 except for a small quantities of a low molecular-weight fraction. This suggests that ¹⁴C-SL-1010 was only slightly metabolized in the synovial tissue.
3. The route of elimination of ¹⁴C-SL-1010 from the joint cavity was mainly via the lymphatic system, since any time after elimination of ¹⁴C-SL-1010 from the joint cavity the level of radioactivity in the iliac lymph node was much higher than that in the liver. The radioactivity derived from HA in the iliac lymph nodes 24hr after injection and identified as HA-specific hyaluronidase treatment, was 5.6 to 11.7% of the total radioactivity. In in vitro study, metabolic activity in the lymph node was higher than that in the liver.
It is suggested that most of the ¹⁴C-SL-1010 injected into the knee joint was eliminated and was mainly metabolized in the lymphatic system.
4. Excretion of radioactivity at 144 hr was 70, 3.5 and 0.8% in expired air, urine and feces, respectively.
5. Sex related differences in the distribution of radioactivity either in blood or plasma were negligible.

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A 1 % ¹⁴C-SL-1010 solution (3mg/kg) was administered repeatedly into the cavitas articulare of left rabbit knee at 4 day intervals for a total of 7 times.
1. Residual radioactivity in synovial fluid was approximately 60% of each dose at 24hrs after the 4th and 7th administrations and was comparable to that observed after the first administration. The clearance of radioactivity from synovial fluid observed after the 7th administration was comparable to a simulated curve projected from results for the first administration study group, and no accumulation was observed as a result of repeated administration.
2. Plasma levels of radioactivity reached the steady state following the 3rd administration and gradually decreased from 5 days after the 7th administration with an elimination half-life of 106. Ohrs. The observed plasma profile of radioactivity was similar to that simulated from results of the single dose study.
3. The primary route of excretion was the expired air. The cumulative excretion of radioactivity in expired air reached the steady state after the 6th administration and reached 81.5% of the total dose at 14 days after the 7th administration. The cumulative excretion of radioactivity in urine and feces were 3.3% and 2.9%, respectively. These results were similar to those observed in the single dose study.
4. The levels of radio activity in various tissues surrounding the dosing side of the knee joint gradually increased with repeated administration. At 24hrs after the 4th administration, the level had risen to 0.9-2.8 times higher levels of that at 24hrs following the first administration, and the peak concentration observed after the 7th administration was 1.4-3.2 times higher than the level at 24hrs following the first administration. The level of radioactivity was highest in the synovial tissue and was followed in order of decreasing radioactivity by the infrapatellar fat pad, meniscus, patellar ligament, cartilage and patella.
5. The level of radioactivity in the principal tissues beyond the knee joint tended to increase gradually with repeated administration, reaching a peak at 24hrs following the 7th administration. The peak values for liver, lung, kidney, spleen, Harderian gland, adrenal gland and heart were 2.6-13.6 times higher than the levels at 24hrs after the first administration. At 14 days after the 7th administration, these concentrations had decreased to 10-60% of peak values.

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