• YAKHAK HOEJI
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• v.37 no.4
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• pp.383-388
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• 1993

Pharmacokinetics of aucubin, an irdoid glucoside, was compared in rats of experimental hepatic failure(EHF). EHF was induced by CCI$_{4}$ or D-galactosamine pretreatment. This work was designed to find out any differences in the pharmacokinetics of aucubin that may explain the different protective effect of aucubin on CCI$_{4}$- and galactosamine-induced EHF : aucubin reportedly protected CCI$_{4}$-inducing hepatotoxicity effectively, but did not for galactosamine-hepatotoxicity. EHF was induced by intraperitoneal injection Of CCI$_{4}$(0.9ml/kg) or galactosamine(250 mg/kg) to Wistar rats 24 hr before the pharmacokinetic study. The rats were fasted during the 24 hr. Aucubin was iv injected at a dose of 15 mg/kg and the plasma aucubin was assayed by HPLC. There were no significant differences in the pathophysiologies(body weight, liver weight, GTP, hematocrit, blood cell distrbution and plasma protein binding of aucubin) between the two EHF models except GOP which was significantly (p<0.05) higher in CCI$_{4}$-than in galactosamine-EHF. On the other hand, pharmacokinetics of aucubin such as total cleatance(CL$_{t}$), distribution volume at steady-state(Vd$_{ss}$), and mean residence time(MRT) differed significantly(p<0.05) between the models : for example, CL$_{t}$ was increased two fold by CCI$_{4}$, but not by galaclosamine ; Vd$_{ss}$, in galactosamine-EHF was higher than that in CCI$_{4}$-EHF ; MRT was decreased by CCI$_{4}$, but increased conversely by galactosamine. The increase of CL$_{t}$(and decrease of MRT) in rats of CCI$_{4}$-EHF was contrary to the general expectation for the hepatic failure : most of the hepatic failures have been known to decrease CL$_{t}$ of the administered drugs. Whether the difference in the pharmacokinetics is responsible for the different protective effect of aucubin against the two EHF models is of interest. However, much more studies on biliary excretion, urinary excretion, and hepatic uptake in cellular level should be preceded before any conclusions are made on the role of different pharmacokinetics on the different pharmacology of aucubin.

• Archives of Pharmacal Research
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• v.20 no.4
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• pp.318-323
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• 1997

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethyinitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life $(t_{1/2})$ in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL $(8.67{\pm}4.85%)$ decreased about four-folds, but in DMNA $(73.00{\pm}9.85%)$ similar result war observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.

• Biomolecules & Therapeutics
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• v.4 no.1
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• pp.78-83
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• 1996

The pharmacokinetics and tissue distribution of DA-3285 (recombinant human erythropoietin, recently manufactured by Research Laboratories of Dong-A Pharmaceutical Company) were studied in the laboratory animals. The plasma, urine, and tissue concentration of DA-3285 were measured by a double-antibody sandwich enzyme immunoassay. After intravenous administration of DA-3285, 20, 100, 500 and 2500 units/kg to rats, the plasma concentrations declined polyexponentially with the terminal half-lives of 2.15, 2.10, 2.31, and 2.35 hr, respectively. Total body clearance (20.7∼26.6 mι/hr/kg) and apparent volume of distribution at steady state (57.2∼70.1 mι/kg) were independent of the dose and AUC increased proportionally with the dose. The renal clearance was much lower than total body clearance, suggesting that extrarenal clearance, presumably metabolism , plays a significant role in elimination of DA-3285. In all rat tissues, the tissue to plasma ratios were smaller than unity, indicating less affinity of DA-3285 to rat tissues and was proved by considerably less value of Vdss. After 3 times a week for consecutive 3 weeks i.v. administration of DA-3285, 100 units/kg to rats, the plasma concentrations and pharmacokinetic parameters of DA-3285 were not significantly different from those in a single administration. After s.c. administration to the rat, plasma concentrations of DA-3285 peaked at 6 hr and the extent of bioavailability was 26.7%. In mice, rabbits and dogs, at DA-3285 dose of 100 units/kg, the mean terminal haw-lives were 2.78, 3.05, and 4.01 hr, respectively. Compared with reported data in the literatures, DA-3285 has similar properties to rh-EPO manufactured by other companies in view of pharmacokinetics.

• Toxicological Research
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• v.23 no.4
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• pp.289-299
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• 2007

Lipopolysaccharide (LPS) endotoxin is an active component in the outer membrane of Gram-negative bacteria. LPS is usually used as an inflammatory animal model. During the inflammation, diarrhea and changes in plasma proteins, in hepatic and/or intestinal microsomal cytochrome P450 (CYP) isozymes, and in the renal and/or biliary excretion of drugs have been reported. Thus, in rats pretreated with lipopolysaccharide endotoxin isolated from Klebsiella pneumoniae (KPLPS rats), the absorption, distribution, metabolism, and excretion of drugs could be expected to be altered. Interestingly time-dependent effects on the hepatic CYP isozymes have been reported in KPLPS rats. Thus, in KPLPS rats, the pharmacokinetics of drugs which are mainly metabolized via CYP isozymes could be expected to be time-dependent. In this review, an attempt to explain changes in pharmacokinetics of drug reported in the literature was made in terms of CYP isozyme changes or urinary and/or biliary excretion changes in KPLPS rats.

• YAKHAK HOEJI
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• v.40 no.5
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• pp.532-538
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• 1996

In cancer chemotherapy, it is necessary to control the phamacokinetic behavior of an antitumor drug for effective treatment. Therefore, two 5-fluorouracil derivatives synthesize d with N-a-cyloxycarbonyl derivatives {1-(N-t-butyloxycarbonyl)leucyloxymethyl-5-FU(BLFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU)}. prodrugs of 5-fluorouracil, antitumor agent, were loaded into liposome of different lipid compositions. After liposomal drugs were injected intramuscularly, their pharmacokinetics and tissue distribution were assessed. The $AUC_{0{\to}{\infty}$ values were 1.29, 72.50, 85.57, 66.40 and 103.60${\mu}$g.hr/ml for 5-FU, BLFU, CLFU, BLFU- and CLFU-loaded liposome, respectively. 5-FU was distributed to spleen and liver with a maximal concentration after 1 hr and eliminated after 24 hr. But both prodrugs and dimyristoylphosphatidylcholine liposome entrapped prodrugs were distributed to spleen and liver at a lower concentration but maintained for a long time with a relatively high concentration in lung. Especially, liposome-entrapped CLFU was distributed to lung with a maximal concentration after 1 hr and redistributed to spleen increasingly, while the concentration of liposome-entrapped BLFU in lung reached a maximal level after 12 hr.

• Korean Journal of Clinical Pharmacy
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• v.20 no.2
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• pp.128-137
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• 2010

This review summarizes gender differences in pharmacokinetics, pharmacodynamics, and adverse drug reactions. Gender differences in pharmacokinetics are categorized by four major factors: absorption/bioavailability, distribution, metabolism, and elimination. There are sex-based differences in gastric emptying time, gastric alcohol dehydrogenase activity, apparent volume of distribution, ${\alpha}1$-acid glycoprotein level, phase I (CYP) and phase II metabolizing enzymes, glomerular filtration rate, and drug transporters. This review also reports gender differences in pharmacokinetics and pharmacodynamics of cardiovascular agents, central nervous system acting agents and antiviral agents. In addition, it has been reported that females experience more adverse reactions such as coughing, tachycardia, nausea, vomiting, rash, hypersensitivity, hepatotoxicity, and metabolic disorder after taking cardiovascular, central nervous system acting and antiviral agents. Therefore, in order to provide optimal drug dosage regimens both in male and female, gender differences in pharmacokinetics, pharmacodynamics, and adverse drug reactions must be considered.

• Biomolecules & Therapeutics
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• v.2 no.4
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• pp.310-315
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• 1994

The pharmacokinetics and tissue distribution of DA-3030 (recombinant human granulocyte colony-stimulating factor, rhG-CSF, recently manufactured by Dong-A research laboratory of Dong-A Pharmaceutical Company) were compared with reported data in the literature. After intravenous(i.v.) administration of DA-3030, at dose of 5, 10 and 100 $\mu\textrm{g}$/kg to rats, some pharmacokinetic parameters, such as terminal half-lives(1.05, 1.19 and 1.83 hr, respectively) and clearance (84.0, 54.8 and 45.5 mι/hr/kg, repectively), were dose-dependent. This could be due to the saturable metabolism of DA-3030 in rats. Similar results were also reported. After subcutaneous(s.c.) and intramuscular(i.m.) administrations of DA-3030, 10 $\mu\textrm{g}$/kg to rats, the extent of bioavailability(absolute bioavailability) were incomplete; the values were 23.3 and 18.2% after s.c. and i.m. injections, respectively, due to the degradation of DA-3030 by protease. After 7-consecutive day i.v. administrations of DA-3030, 10 $\mu\textrm{g}$/kg/day, to rats, the plasma concentrations and pharmacokinetic parameters of DA-3030 were not significantly different from those in single administration. In mice and dogs at DA-3030 dose of 10 $\mu\textrm{g}$/kg, the plasma concentrations of DA-3030 were also declined rapidly with terminal half-lives of 1.31 and 1.15 hr, respectively. DA-3030 was highly concentrated in the kidney after i.v. administration of DA-3030, 10 $\mu\textrm{g}$/kg, to rats, and the results were similar to those obtained using radiolabelled rhG-CSF in the literature. Above data indicate that DA-3030 has similar properties to rhG-CSF manufactured by other companies in view of pharmacokinetics.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.86-95
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• 2020

Background: Ginsenoside Rb1 (Rb1), one of the most abundant protopanaxadiol-type ginsenosides, exerts excellent neuroprotective effects even though it has low intracephalic exposure. Purpose: The present study aimed to elucidate the apparent contradiction between the pharmacokinetics and pharmacodynamics of Rb1 by studying the mechanisms underlying neuroprotective effects of Rb1 based on regulation of microflora. Methods: A pseudo germ-free (PGF) rat model was established, and neuroprotective effects of Rb1 were compared between conventional and PGF rats. The relative abundances of common probiotics were quantified to reveal the authentic probiotics that dominate in the neuroprotection of Rb1. The expressions of the gamma-aminobutyric acid (GABA) receptors, including GABAA receptors (α2, β2, and γ2) and GABAB receptors (1b and 2), in the normal, ischemia/reperfusion (I/R), and I/R+Rb1 rat hippocampus and striatum were assessed to reveal the neuroprotective mechanism of Rb1. Results: The results showed that microbiota plays a key role in neuroprotection of Rb1. The relative abundance of Lactobacillus helveticus (Lac.H) increased 15.26 fold after pretreatment with Rb1. I/R surgery induced effects on infarct size, neurological deficit score, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) were prevented by colonizing the rat gastrointestinal tract with Lac.H (1 × 10⁹ CFU) by gavage 15 d before I/R surgery. Both Rb1 and Lac.H upregulated expression of GABA receptors in I/R rats. Coadministration of a GABA_A receptor antagonist significantly attenuated neuroprotective effects of Rb1 and Lac.H. Conclusion: In sum, Rb1 exerts neuroprotective effects by regulating Lac.H and GABA receptors rather than through direct distribution to the target sites.

• Archives of Pharmacal Research
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• v.9 no.1
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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.

• Journal of Pharmaceutical Investigation
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• v.12 no.4
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• pp.153-174
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• 1982