• 약학회지
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• 제28권4호
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• pp.207-215
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• 1984

Effects of Ssang Wha Tang (SWT), a blended Chinease traditional medicine, on the pharmacokinetics of sulfobromophthalein (BSP) in the rats of hepatic failure induced by carbon tetrachloride were examined. The disposition of plasma BSP in carbon tetrachloride-treated rats (Group I) and in carbon tetrachloride+SWT-treated rats (Group II) followed a three-compartment model, while those in control group followed two-compartment model. GOT, GPT level and some pharmacokinetic paramiters like plasma clearance but except distribution volume (Vdss) recovered in Group II compared to Group I. Therefore, SWT seemed to have an apparent restoring effect of hepatic function damaged by carbon tetrachloride treatment. From the fact that Vdss of BSP in Group II was considered as an one of the probable mechanisms. More intensive increase in BSP-free fraction ($f_p$) in Group II than that in Group I might also explain the increases of BSP clearance and Vdss in Group II compared to Group I. Assuming no changes in hepatic plasma flow(Q) in each group, hepatic intrinsic clearance($CL^h_{int}$) decreased in Group I did not recovered not at all in Group II. Therefore SWT seemed not to have any restoring effect of true hepaticfunction to biotransform and excrete BSP, and the apparent restoring effect of SWT might be due only to the replacement of BSP-plasma protein binding. Whether $f_p$ is actually higer in Group II than in Group I, and Q is constant in each group are being examined in our laboratory. The changes of Q, which might lead to another conculusions, also should be taken into consideration to clarify the apparent hepatorestoring effect of SWT.

• Biomolecules & Therapeutics
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• 제28권4호
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• pp.361-369
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• 2020

Tofacitinib, a Janus kinase inhibitor, was developed for the treatment of rheumatoid arthritis. Recently, it has been associated with an increased change in arthritis development in patients with diabetes. Herein, we evaluated the pharmacokinetics of tofacitinib after intravenous (10 mg/kg) and oral (20 mg/kg) administration to rats with streptozotocin-induced diabetes mellitus and control rats. Following intravenous administration of tofacitinib to rats with streptozotocin-induced diabetes mellitus, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was significantly smaller (33.6%) than that of control rats. This might be due to the faster hepatic intrinsic clearance (112%) caused by an increase in the hepatic cytochrome P450 (CYP) 3A1(23) and the faster hepatic blood flow rate in rats with streptozotocin-induced diabetes mellitus than in control rats. Following oral administration, area under the plasma concentration-time curve from time zero to infinity of tofacitinib was also significantly smaller (55.5%) in rats with streptozotocin-induced diabetes mellitus than that in control rats. This might be due to decreased absorption caused by the higher expression of P-glycoprotein and the faster intestinal metabolism caused by the higher expression of intestinal CYP3A1(23), which resulted in the decreased bioavailability of tofacitinib (33.0%) in rats with streptozotocin-induced diabetes mellitus. In summary, our findings indicate that diabetes mellitus affects the absorption and metabolism of tofacitinib, causing faster metabolism and decreased intestinal absorption in rats with streptozotocin-induced diabetes mellitus.

• Journal of Pharmaceutical Investigation
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• 제17권2호
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• pp.89-93
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• 1987

Effects of Ssang Wha Tang (SWT), a blended Chinese traditional medicine, on the pharmacokinetics of sulfobromophthalein (BSP) were studied in the rats. BSP was administered via portal vein to the control and the SWT-treated rats. The in vitro distribution of BSP to blood cells and the hemato-physiological conditions, liver weight, GOT. GPT activity were also examined. The systemic clearance $(CL_s)$ of BSP was increased with the administration of SWT, but no significant differences were observed in the liver weight and in vitro distribution of BSP to blood cells. These results suggest that the intrinsic clearance of free BSP of the liver is increased with the administration of SWT in the rats.

• 약학회지
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• 제35권1호
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• pp.38-44
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• 1991

It has been reported that the pharmacokinetic behaviors of drugs which are mostly metabolized in the liver are significantly different in patients with renal failure. Theophylline(TP) is mainly metabolized in the liver (approximately 90%) and renal clearance of the drug is negligible (less than 10%). Therefore, we have investigated the changes in pharmacokinetics of theophylline in normal, G-ARF and U-ARF rats after an intravenous administration. The total body clearance of TP decreased approximately 40% in U-ARF rats. The reduced CL$_{T}$, value in U-ARF rats could be due to reduced hepatic intrinsic clearance by up to 40% since it has been published that plasma protein binding of TP and liver blood flow does not change in U-ARF rats.

• Journal of Pharmaceutical Investigation
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• 제22권4호
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• pp.301-306
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• 1992

The influence of phenobarbital (PB) pretreatment (75 mg/kg/day, i.p. for 4 days) on the metabolite kinetics of diltiazem (DTZ) was studied in rats in order to elucidate the effect of esterase induced by PB on the formation of DTZ to desacetyldiltiazem (DAD), DAD was injected via portal vein (3 mg/kg) to the control and PB-pretreated rats, The intrinsic hepatic clearance of DAD was significantly increased by PB pretreatment and the absolute bioavailability of DAD was significantly decreased in the PB-pretreated rats. According to the hepatic biotransformation model of DTZ, the fraction of systemic clearance of DTZ which forms DAD $(G_{mi})$ was different from that of DTZ which furnishes the available DAD to the systemic circulation $(F_{mi})$ in control rats. This result shows that DTZ was suspected of the sequential hepatic first-pass metabolism. On the other hand, PB pretreatment enhanced the $G_{mi}$ value of DTZ by 44%. It may be concluded that the deacetylation of DTZ to DAD in rats is increased by the esterase induced by PB but the transfer rate of DAD immediately formed from DTZ into systemic circulation is not affected by PB due to the 27% decreased absolute bioavailability of DAD resulting from PB pretreatment.

• Archives of Pharmacal Research
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• 제21권6호
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• pp.677-682
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• 1998

The present study was designed to examine the metabolism of 1-anilino-8-naphthalene sulfonate (ANS), an anionic compound which is transported into liver via "multispecific organ ic anion transporter", with rat hepatic microsomes. TLC analysis indicated that the fluorescent metabolites were not produced to a measurable extent, which made it possible to assess the ANS metabolism by measuring the fluorescence disappearance. The metabolism of ANS was remarkably inhibited by the presence of SKF-525A as well as by the substitution of 02 by CO gas. ANS metabolism by microsomes also required NADPH as a cofactor. These results indicated that the microsomal monooxygenase system might be mainly responsible for the ANS metabolism. The maximum velocity ($V_{max}$) and Michaelis constant ($K_m$) were calculated to be $4.3{\pm}0.2$ nmol/min/mg protein and $42.1{\pm}2.0\;{\mu}M$, respectively. Assuming that 1g of liver contains 32mg of microsomal protein, the $V_{max}$ value was extrapolated to that per g of liver ($V_{max}^I$). The intrinsic metabolic clearance ($CL_{int}$) under linear conditions calculated from this in vitro metabolic study was 3.3ml/min/g liver, being comparable with that (3.0ml/min/g liver) calculated by analyzing the in vivo plasma disappearance curve in a previous study. Furthermore, the effects of other organic anions on the metabolism of ANS were examined. Bromophenolblue (BPB) and rose bengal (RB) competitively inhibited the metabolism of ANS, while BSP inhibited it only slightly. The inhibition constant ($K_i$) of BPB ($6\;{\mu}M$) was much smaller than that of RB ($200\;{\mu}M$). In conclusion, the microsomal monooxygenase system plays a major role in the metabolism of ANS, and other unmetabolizable organic anions (BPB and RB) compete for this metabolism.

• Archives of Pharmacal Research
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• 제24권6호
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• pp.584-589
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• 2001

Isopropryl 2-(1-3-dithiethane-2-ylidene)-2 [N-(4-methyl-thiazole-2-yl) carbamoyl] acetate (YH439) is currently under phase ll clinical trials by the Yuhan Research Center for use as a hepatoprotective agent. Unfortunately, the oral bioavailbility of YH439, which is sparingly soluble in water (i.e., $0.3{\;}\mu\textrm{g}/ml{\;}or{\;}0.91{$\mu}M$ at room temperature), reportedly, is negligibleregardless of the dose administered to rats in the 10-300 mg/kg range. The bioavailability of the compound increased up to 24%, when administered in the form of a micellar solution ($700{\;}\mu\textrm{g}/ml$or 2.1 mM for YH439) at a dose of 10 mg/kg, suggesting that its limited solubility is associated with its negligible bioavailability. In order to obtain additional informmation concerning the bioavailability of YH439, the mechanism(s) involved in gastrointestinal (Gl) absorption were investigated in the present study. For this purpose, the transport of YH430 across a Caco-2 cell monolayer was measured in a $Transwell^{\circledR}$. A permeability of $4.07{\times}10^{-5}{\;}cm/s$ was obtained for the absorptive (i.e., apical to basolateral direction) transport of $0.42{\mu}M$ YH439, implicating that the in vivo Cl absorption is nearly complete. The absorptive transport exhibited a slight concentration-dependency with an intrinsic clearance ($CL_{i}$) of $0.38{\mu}L/{\textrm{cm}^2}/sec$, which accounted for 28.1% of the total intrinsic clearance (i.e., $CL_i$ plus the intrinsic clearance for the linear component) of the transport. Thus, saturation of the absorption process appears to be a minor factor in limiting the bioavailability of the compound. The apparent permeability of YH439 from the basolateral to the apical direction (i.e., efflux, $6.67{\times}10^{-5}{\;}cm/s$) was comparable to that for absorptive transport, but, interestingly, a more distinct concentration-dependency was observed for this transport. However, the efflux does not appear to influence the bioavailability of the compound, as evidenced by the sufficiently high permeability in the absorption direction. Rather, a reportedly extensive first-pass hepatic metabolism appears to be a principal factor in limiting the bioavailability. In this respect, reducing the first-pass metabolism by some means would lead to a higher bioavailability of the compound. Thus, elevation of the absorption rate of YH439 becomes a necessity. From a practical point of view, increasing the concentration of YH439 in the Cl fluid appears to be a feasible way to increase the absorption rate, because the compound is primarily absorbed via a linear mechanism. In summary, the solubilization of YH439, as previously demonstrated for a micellar solution of the compound, appears to be a practical way to increase the oral bioavailability of YH439.