• Journal of Pharmaceutical Investigation
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• 제27권2호
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• pp.109-117
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• 1997

In order to elucidate the effect of phenobarbital (PB) on the nonlinear pharmacokinetic behavior of naproxen (NAP), we compared the dose dependent hepatic intrinsic clearance, biliary excretion and protein binding of NAP in control rats to those in the PB-pretreated rats which were intraperitoneally pretreated with PB sodium (75 mg/kg) once a day for four days. NAP was injected via femoral (1.5 mg/kg) and portal(0.25, 0.5, 1.5, 15 and 30 mg/kg) vein to the control and PB-pretreated rats, respectively. And also, we measured the plasma free fraction of NAP with the equilibrium dialysis method and the biliary excreted total amounts of NAP in both rats. Plasma free fraction of NAP was decreased in lower concentration than $150\;{\mu}g/ml$ of NAP due to PB pretreatment. In higher concentration, however, plasma free fraction was increased. These in vitro results suggest that the total protein concentration was increased but the total binding capacity of NAP to protein was decreased by PB-pretreatment. The total plasma clearance and the hepatic intrinsic clearance of NAP had similar values in both groups, respectively. And, both clearances of NAP were significantly increased by PB-pretreatment. Even though the plasma free fractions of NAP in both groups were constantly remained within the concentration range according to the increase of administration dose, the hepatic intrinsic clearances of NAP were significantly increased in both groups with the increased dose. And, the biliary excreted total amounts of NAP were significantly increased by PB-pretreatment at the lower dose, but decreased at the higher dose. These in vivo results suggest that NAP represents the uncommon nonlinear pharmacokinetic behavior that the hepatic intrinsic clearance was enhanced with the increased dose, and that PB enhances further the hepatic intrinsic clearance of NAP with the increased dose due to its enzyme induction effect.

• Journal of Pharmaceutical Investigation
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• 제10권1호
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• pp.13-23
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• 1980

Bromphenol blue (BPB) was studied with rabbits in normal and disease states to understand the basic principles of hepato-biliary transport process, and the effect of disease states on the drug disposition. The time course of plasma concentration and of biliary excretion was studied in normal and $CCl_4$ intoxicated rabbits. A conspicuous retention of BPB clearance from the plasma was observed, and the slope of the first-phase of plasma curve was decreased in the intoxicated rabbits. The shape of biliary excretion was same in normal and intoxicated states, but the amount of BPB excreted into bile in the intoxicated states was much smaller than in normal states. A relationship was found which enables one to predict the pattern of uptake of BPB by the liver, and the pattern of excretion into the bile in normal states, but was not in $CCl_4$ intoxicated states. It may be that the application of this experiments would extend the effect of disease states on the drug disposition.

• The Korean Journal of Physiology
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• 제5권2호
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• pp.45-54
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• 1971

That different mechanisms are involved in the secretory processes by the liver and the kidney of various dyes has been indicated by Sporter (1959), Kim and Hong (1963). Andrews (1958). suggested that a striking difference in the dye-secretory mechanism existed even in the same organ from species to species. Hence, the attempt has been made to study in the rabbit the secretory processes by the live. and the kidney of either phenol red (PSP), bromsulfalein (BSP) or green in the presence of Na-acetate, Na-taurocholate, P-Aminohippurate (PAH) or Benemid. In 37 rabbits, weighing about 2kg., anesthetized with ether, a dye was administered in such 8 manner that the plasma concentration was kept at a relatively constant level throughout the whole experimental period. Hepatic bile sad urine samples were quantitatively collected through the canulae which were previously inserted into the common bile duct (with the cystic duct ligated) and the urinary bladder, respectively, while arterial samples were taken from a femoral artery. After 50 min from the onset of dye administration, these samples were obtained every 10 mit for a period of 40 min. This was followed by the administration of either Na-acetate, Na-tauro-cholate, PAH or Benemid with a repetition of the same sample collecting procedures just stated. The results may be summarized as follows: 1) Na·acetate augmented urinary clearance of PSP by nearly 300 per cent, but lowered urinary BSP clearance by about 50 per cent. It enhanced biliary BSP clearance by 40% and had no effect on biliary psp clearance. 2) Na-taurocholate lowered biliary and urinary clearance of PSP by 10 per cent and 30 per cent respectively, and had no effect on both biliary and urinary clearance of BSP. 3) PAH lowered both biliary and urinary excretion of BSP and PSP, while it lowered the biliary excretion of indocyanine green which was excreted only in the bile. 4) Benemid suppressed BSP excretion by the liver and the kidney. 5) raper chromatographic analysis of PSP and of BSP in the bile and urine samples gave the following results: a) PSP Ivas excreted in the urine and bile only in free forms, and no modification in the excretory pattern was brought about by Na-taurocholate. b) BSP was excreted in the urine in 4 different conjugated froms and in the bile in both 3 different conjugated forms and in a free form. Na-taurocholate modified the excretory pattern of the urinary BSP.

• Journal of Pharmaceutical Investigation
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• 제16권3호
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• pp.110-117
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• 1986

Plasma disappearance of amaranth (AM), a model compound of organic anionic drugs, was retarded by intravenous infusion of taurodeoxycholate (TDC), a representative bile acid, in the rat. Biliary excretion accounted for 30-60% of the systemic excretion of AM. AM seemed to be metabolised in the hepatocyte to form a compound that is excreted more rapidly into the bile than AM itself, considering apparent biliary clearance, $CL_{bil}$, is much larger than systemic clearance, $CL_s$. Decrease in $CL_{bil}$ by TDC infusion might be due to elevated plasma level rather than decreased biliary excretion of AM. Decreased distribution or urinary excretion of AM by TDC was supposed to be one of the probable reasons of elevated plasma level. Competitive inhibition between AM and TDC on tissue distribution and urinary excretion might explain the mechanism. The effect of TDC on the $CL_{bil}$ of methylene blue, a cationic dye, was quite different from that of AM, as reported previously by us. More intensive study would be necessary to elucidate the difference of biliary excretion between organic anions and cations.

• Journal of Pharmaceutical Investigation
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• 제31권4호
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• pp.209-216
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• 2001

The purpose of the present study was to investigate the hepatic uptake and biliary excretion of l-anilino-8-naphthalene sulfonate (ANS) in vivo. The plasma concentration and liver concentration of ANS were determined after its i.v. bolus administration at a dose of $30\;{\mu}mol/kg$ in rats. The hepatic uptake clearance $(CL_{uptake})$ of ANS was 0.1 ml/min/g liver. On the basis of the unbound concentration of ANS, the permeability-surface area product $(PS_{influx})$ was calculated to be l0.4 ml/min/g liver, being comparable of in vitro data. On the other hand, we determined the plasma concentration, liver concentration and biliary excretion rate of ANS at steady-state after its i. v. infusion $(0.2-1.6\;{\mu}mol/min/kg)$ in rats. The excretion clearance $(CL_{excretion})$ of ANS showed Michaelis-Menten kinetics with increasing the infusion rate. The permeability-surface area product $(PS_{excretion})$ based on the unbound concentration in the liver was calculated to be 0.0165 ml/min/g liver, which is negligible compared with the intrinsic clearance $(CL_{int}=3.3\;ml/min/g\;liver)$ by rat liver microsomes. The sequestration process of ANS, therefore, was considered to be mainly due to the metabolic process in the liver $(PS_{seq}{\risingdotseq}CL_{int})$. Furthermore, $PS_{efflux}$ value calculated from $PS_{influx}$ and $PS_{seq}$ was 4.4 ml/min/g liver, which was comparable of in vitro data. In conclusion, in vivo parameters such as $PS_{influx}$, $PS_{efflux}$ and $PS_{seq}$ in the present study showed good in vivo-in vitro relationship. Thus, the kinetic analysis method proposed in the present study would be useful to analyze the hepatic transport of drugs in vivo.

• 약학회지
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• 제29권6호
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• pp.362-366
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• 1985

These paper was attempted to investigate the mechanism of increased blood level of sulfisomidine by cimetidine pretreatment pharmacokinetically. Especially, effect of cimetidine pretreatment on both renal clearance and biliary clearance of sulfisomidine was studied in rabbits. The results are as follows. The blood level of sulfisomidine administered intravenously in dose of 25mg/kg was elevated significantly by cimetidine pretreatment. Relative bioavailability and biological half-life were increased significantly by cimetidine pretreatment. Overall elimination rate constant ($betha$) and distribution rate constant ($K_{13}$) of sulfisomidine were decreased significantly by cimetidine pretreatment. The renal and biliary clearance of sulfisomidine were decreased significantly compared with those of control rabbits by cimetidine pretreatment. The results may be also related to the inhibition of sulfisomidine metabolism enzyme activity or reduction of blood flow in the liver.

• Advances in pediatric surgery
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• 제12권2호
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• pp.202-212
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• 2006

The prognostic factors for extrahepatic biliary atresia (EHBA) after Kasai portoenterostomy include the patient's age at portoenterostomy (age), size of bile duct in theporta hepatis (size), clearance of jaundice after operation (clearance) and the surgeon's experience. The aim of this study is to examine the most significant prognostic factor of EHBA after Kasai portoenterostomy. This retrospective study was done in 51 cases of EHBA that received Kasai portoenterostomy by one pediatric surgeon. For the statistical analysis, Kaplan-Meier method, Logrank test and Cox regression test were used. A p value of less than 0.05 was considered to be significant. Fifteen patients were regarded as dead in this study, including nine cases of liver transplantation. There was no significant difference of survival to age. The age is also not a significant risk factor for survival in this study (Cox Regression test; p = 0.63). There was no significant difference in survival in relation to the size of bile duct. However, bile duct size was a significant risk factor for survival (Cox Regression test; p = 0.002). There was a significant difference in relation to survival and clearance (Kaplan-Meier method; p = 0.02). The clearing was also a significant risk factor for survival (Cox Regression test; p = 0.001). The clearance of jaundice is the most significant prognostic factor of EHBA after Kasai portoenterostomy.

• 대한핵의학회지
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• 제22권2호
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• pp.181-185
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• 1988

Since hepatocyte clearance, leading edge parencymal transit time and biliary excretion can be evaluated separately with hepatobiliary scan using $^{99m}Tc-DISIDA$, hepatobiliary scan may be useful in differentiating intrahepatic cholestasis from extrahepatic cholestasis. Excretory liver function was analysed in 13 healthy subjects and 11 patients with clinically suspected hepatocellular disease and 9 patients with extrahepatic biliary obstruction confirmed by surgery, radiological and clinical evidence. Indices of total liver activity (% TLA), liver parechymal uptake (% LPU), heart pool clearance (% HPC) and liver-heart rate (% LHR) were calculated from time activity curve over heart and liver. Compared with healthy subjects, significant reduction (p<0.05) in total liver activity (% TLA) and liver-heart rate (% LHR) was observed in all patients group. But no useful indices was demonstrated in differentiating hepatocellular disease from extrahepatic biliary obstruction.

• Archives of Pharmacal Research
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• 제20권4호
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• pp.358-362
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• 1997

Metabolite identification and urinary and biliary excretion of the new fluoroquinolone antibacterial agent DW116 [1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1 -piperazinyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, hydrochloride] after oral administration have been studied in Sprague-Dawley rats. The excretion kinetics were monoexponential. Most of the drug was eliminated via the hepatic and renal routes. Mean renal clearance of DW116 was 73.4 ml/hr/kg and mean biliary clearance was 83.8 ml/hr/kg. The major metabolite excreted in the bile was identified as the glucuronide ester of the parent drug using base-hydrolysis of the conjugate metabolite followed by co-HPLC with standard compound, $^{19}$ F-NMR and LC-MS methods. The glucuronide conjugate was also found in urine. The mean urinary recoveries of free and total (free plus glucuronide ester) DW116 were $28.6{\pm}2.7% $and $36.4{\pm}1.8%$ of the administered dose and the corresponding biliary recoveries were $14.4{\pm} 5.5%$ and $37.0{\pm}7.6%$, respectively.

• Archives of Pharmacal Research
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• 제9권1호
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• pp.49-54
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• 1986

Effect of sodium taurodeoxycholate (TDC) infused intravenously on the pharmacokinetics of methylene blue (MB) was studied in the rat to investigate the role of ion-pair complexation in the body on drug elimination and disposition. Distribution volume (Vd) of MB was increased significantly (p< 0.05) by TDC infusion. Considering together with the fact that apparent partition coefficient (APC) of MB between phosphate buffer (pH 7.4) and n-octanol was increased markedly by TDC, the increase in Vd seemed to be the result of decreased polarity of MB by ion-pair formation with TDC. But total body clearance (CLt) and biliary excretion clearance (CLbil) of MB were not increased significantly by TDC.