• Journal of Pharmaceutical Investigation
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• v.36 no.4
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• pp.263-269
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• 2006

Deficiencies in the early ADMET(absorption, distribution, metabolism, elimination and toxicity) information on drug candidate extract a significant economic penalty on pharmaceutical firms. Microscale cell culture analogue-microscale gastrointestinal(${\mu}CCA-{\mu}GI$) device using Caco 2, L2 and HEp G2/C3A cells, which mimic metabolic process after absorption occurring in humans was used to investigate the toxicity of the model chemical, acetaminophen(AAP). The toxicity of acetaminophen determined after induction of CYP 1A1/2 in Caco 2 cells was not significant. In a coculture system, although no significant reduction in viability of HEp G2/C3A and L2 cells was found, approximately 5 fold increase in the CYP 1A1/2 activity was observed. These results appear to be related to organ-organ interaction. The oral administration of a drug requires addition of the absorption process through small intestine to the current ${\mu}CCA$ device. Therefore, a perfusion coculture system was employed for the evaluation of the absolution across the small intestine and resulting toxicity in the liver and lung. This system give comprehensive and physiologic information on oral uptake and resulting toxicity as in the body. The current ${\mu}CCA$ device can be used to demonstrate the toxic effect due to organ to organ interaction after oral administration,

• Journal of Pharmaceutical Investigation
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• v.22 no.2
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• pp.139-148
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• 1992

A prodrug of cefazolin pivaloyloxymethyl ester (CFZ-PV) was synthesized to improve oral absorption and bioavailability of parent drug by esterification of sodium cefazolin (CFZ) with chloromethyl pivalate. The successful synthesis of CFZ-PV was confirmed by spectroscopic analysis. Partition coefficient studies showed that CFZ-PV is more lipophilic than CFZ. The pharmacokinetic characteristics of CFZ-PV and CFZ preparations were compared following oral administrations of these compounds to rabbits. The analysis of CFZ in plasma was conducted by HPLC method. The ester compound (prod rug) was not detected in plasma following oral administration of CFZ-PV, and although CFZ-PV had not microbiological activity in vitro, the plasma taken after CFZ-PV administration had microbiological activity. From above observations, it was noted that CFZ-PV is rapidly hydrolyzed to CFZ in the body. And it was found that the oral absorption of CFZ-PV was increased, yielding 2-fold higher bioavailability than CFZ. From the results of this experiment, it was concluded that CFZ-PV could be a novel prodrug of CFZ which can improve the oral bioavailability of CFZ.

• Archives of Pharmacal Research
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• v.17 no.5
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• pp.364-370
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• 1994

A microscopic mass balance approach has been developed to estimate the extent and rate of absorption for camier-mediated comounds. For the case competitive inhibition in the presence of an inhibitor which shares the same camier, the fraction dose absorbed (F) and absorption rate constant ($K_a$) of a drug can be calculated from its concentration profile in the intestinal lumen. Absorption parameters obtained by single-pass perfusion experiments were used in the simultaion of the absorption of some aminopenicilins. Predicted fractions dose absorbed and absorption rate constants of ampicilin and amoxicilin were significantly reduced in the presence of a 6-times higher molar dose of cyclacilin. The drug-drug interactions on the competitive absroption of camier-mediated compounds were determined with regard to F and $K_a$. Predicted decreases in F for some aminopenicilins corrlated well with decrease in the urinary recovery in humans reported in the literature. Predicted decrease in the mean absorption rate constant ($\barK_a$) explain the delays in the time of peak plasma concentration ($T_{max}$) reported in humans.

• The Journal of the Korean Society for Microbiology
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• v.35 no.3
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• pp.203-214
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• 2000

Porphyromonas gingivalis has been implicated in periodontal diseases. Accumulating evidence suggests that cardiovascular disease is the most prevalent medical problem in patients with periodontal diseases. In order to check the possibility that P. gingivalis is involved in coronary heart disease, the present study was performed to observe P. gingivalis adherence and invasion of human coronary artery endothelial cells (HCAEC) and production of cytokines and growth factors by HCAEC upon P. gingivalis infection. $^3H$-labeled P. gingivalis 381 was incubated with HCAEC for 90 min. The radioactivity of the washed HCAEC was a measure of the absorbed (adhering and invading) P. gingivalis. The absorption radioactivity of the HCAEC infected by P. gingivalis was determined to be 59.58% of the input bacterial cells. In contrast, the absorption radioactivity of the cells infected by S. gordonii Challis which was employed as a control was negligible (0.59%). DPG3, a P. gingivalis mutant defective of fimbriae, appeared to be impaired to some extent in capability of adherence/invasion as compared to that of the parental strain 381, showing 43.04% of the absorption radioactivity. The absorption radioactivity of the HCAEC infected by P. gingivalis 381 in the presence of excessive fimbriae at the concentrations of $50\;{\mu}g$ and $100\;{\mu}g/ml$ was 57.27 and 45.44%, respectively. Invasion of HCAEC by P. gingivalis 381 was observed by an antibiotic (metronidazole) protection assay and transmission electron microscopy (TEM). In the antibiotic protection assay, invasion by the bacterium was measured to be 0.73, 1.09, and 1.51% of the input bacterial cells after incubation for 30, 60, and 90 min, respectively. Invasion by DPG3 was shown to be 0.16% after 90-min incubation. In comparison of invasion efficiency at 90 min of the incubation, the invasion efficiency of DPG3 was 0.37% while that of its parental strain 381 was 2.54%. The immunoblot analysis revealed fimbriae of P. gingivalis did not interact with the surface of HCAEC. These results suggest that fimbriae are not the major contribution to the adherence of P. gingivalis to HCAEC but may be important in the invasion of HCAEC by the bacterium. The presence of cytochalasin D ($1\;{\mu}g/ml$) and staurosporine ($1\;{\mu}M$) reduced the invasion of HCAEC by P. gingivalis 381 by 78.86 and 53.76%, respectively, indicating that cytoskeletal rearrangement and protein kinase of HCAEC are essential for the invasion. Infection of P. gingivalis induced HCAEC to increase the production of TNF-${\alpha}$. by 60.6%. At 90 min of the incubation, the HCAEC infected with P. gingivalis cells was apparently atypical in the shape, showing loss of the nuclear membrane and subcellular organelles. The overall results suggest that P. gingivalis may cause coronary heart disease by adhering to and invading endothelial cells, and subsequently damaging the cells.

• Journal of Pharmaceutical Investigation
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• v.18 no.4
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• pp.197-201
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• 1988

Pivaloyloxymethyl ester of cefoperazone was synthesized by treating sodium cefoperazone with chloromethyl pivalate and its chemical structure was determined by spectroscopic trials. The pharmaceutical properties of the ester were investigated to assess its potential as a prodrug of cefo perazone. Cefoperazone pivaloyloxymethyl ester was microbiologically inactive itself in vitro, but hydrolyzed into the parent drug in vivo. After a single oral dose of each drug to rabbits, serum concentrations of cefoperazone were determined by high performance liquid chromatographic assay. The ester showed higher and more sustained blood level than cefoperazone. Therefore, the total area under the serum concentration-time curve of the derivative was 16.8 times larger than that of the parent drug.

• Journal of the Korean Society of Food Science and Nutrition
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• v.23 no.3
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• pp.396-401
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• 1994

The effect of vitamin B12 status and pectin feeding on vitamin B12 absorption in rats were studied. Rats in low, medium, and high vitamin B12 status were fed either fiber-free or 10% pectin diet and absorption of a single oral dose of vitamin B12 status of rats was verified by urinary methylmalonic acid and liver vitamin B12 measurements. Absorption of vitamin B12 tended to increase as the rats became deficient in vitamin B12 , although the difference was not significant . Pectin inhibited absorption of vitamin B12 regardless of the vitamin B12 status of the rats. The results demonstrated that inhibition of vitamin B12 absorption by pectin would be a possible mechanism for the impairment of vitamin B12 status due to chronic pectin feeding.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.272-272
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• 1996

While ranitidine is well known to be absorbed rapidly, the underlying cause of variable bioavailability in intra- and inter-subjects has not been clarified yet. Intestinal permeability is a key controlling factor for oral absorption of highly soluble drugs, In the present study, intestinal ferfusions have been conducted to determine the intestinal permeabilities(Peffs) of ranitidine in the rats, dogs and humans and compared to the estimated fractions of dose absorbed (FAs) in humans. A new in vivo methodology, using a regional segmental perfusion technique, has been used in the dogs and humans. In situ single-pass perfusion experiments have been performed in the rats. In the dog and human studies, perfusion experiments have been conducted on two periods to determine the intrasubject variability, There was low significant intrasubject variation as compared to intersubject variation. The Peffs of ranitidine were 33%, 51%, and 45% inthe rats, dogs and humans, respectively. The FAs were approximately the same for all three species models, suggesting rats and dogs are good animal models for estimating the oral absorption of ranitidine in humans. In addition, the estimated extent of absorption of this drug is consistent with the average bioavailability, indicating that ranitidine has permeability-limited absorption characteristics. Supported by FDA Grant FD01462.

• Journal of Ginseng Research
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• v.15 no.2
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• pp.112-116
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• 1991

The metabolic fate of ginsenosides including gastrointestinat absorption, organ distribution, excretion and metabolism in liver was investigated by tracer studies using the radio-labeled ginsenosides. 3H-ginsenosides were shown to be absorbed from the mouse digestive tract and then to be excreted rapidly into urine and/or bile. Bile juice was concluded to play a significant role in absorption of ginsenosides. The total concentration of radioactivity persisted in tissues 24 hrs after oral administration was less than 1.3% of the administered dose and Rbl showed the highest value. The concentrations of radioactivity were relatively high in the liver and kidney. After administration of Rbl radioactivity was detected in the brain. After oral administration of 8H-ginsenosides, major component excreted into urine was found to be the intact ginsenosides and decomposed and/or metabolized products were found in GIT in the case of Rbl. 3H-ginsenoside Rbl was shown to be metabolized in the liver and the metabolite was suggested to be an acylated compound of Rbl by a certain organic acid.

• Journal of Society of Preventive Korean Medicine
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• v.19 no.1
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• pp.145-159
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• 2015

Objective : In the previous study, co-administration of Gongjindan-gamibang (GJD) with sorafenib increased oral bioavailability of sorafenib through augment the absorption, therefore, the effects of GJD co-administration on the pharmacokinetics of sorafenib were observed after single and 7-day repeated oral co-administration with 3.5 hr-intervals in the present study. Method : After 50 mg/kg of sorafenib treatment, GJD 100 mg/kg was administered with 3.5 hr-intervals. The plasma were collected at 30 min before administration, 30 min, 1, 2, 3, 4, 6, 8 and 24 hrs after end of first and last 7th sorafenib treatment, and plasma concentrations of sorafenib were analyzed using LC-MS/MS methods. PK parameters of sorafenib ($T_{max}$, $C_{max}$, AUC, $t_{1/2}$ and $MRT_{inf}$) were analysis as compared with sorafenib single administered rats. Results : GJD markedly inhibited the absorption of sorafenib, from 1 hr to 24 hrs after end of first 3.5 hr-interval co-administration, the $C_{max}$ (-43.27%), $AUC_{0-t}$ (-56.29%) and $AUC_{0-inf}$ (-66.70%) of sorafenib in co-administered rats were dramatically decreased as compared with sorafenib single treated rats. However, GJD significantly increased the absorption of sorafenib, from 4 hr to 8 hrs after end of last 7th 3.5 hr-interval co-administration, the $AUC_{0-t}$ (34.08%) and $AUC_{0-inf}$ (37.31%) of sorafenib in co-administered rats were dramatically increased as compared with sorafenib single treated rats. Conclusion : Although GJD decreased the oral bioavailability of sorafenib through inhibition of gastrointestinal absorptions after end of first 3.5 hr-interval co-administration, it is observed that GJD increases the oral bioavailability of sorafenib as facilitated the absorption after end of last 7th repeated co-administration. Hence, the co-administration of GJD and sorafenib should be avoided in the combination therapy of sorafenib with GJD on anticancer therapy.

• Korean Journal of Clinical Pharmacy
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• v.8 no.2
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• pp.133-138
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• 1998

Phthalimidyl ester of ceftezole (CFZ-PT) was synthesized as a prodrug by esterification of ceftezole (CFZ) with N-bromophthalimide. CFZ-PT was more lipophilic than CFZ when the lipophilicity was assessed by partition coefficients between n-octanol and water at various pH. The pharmacokinetic characteristic of CFZ-PT and CFZ preparations were compared following oral administrations of these compounds to rabbits. CFZ-PT is expected to be metabolized rapidly to CFZ in the body. The metabolism process appears to be hydrolysis of the ester to CFZ, the parent drug of CFZ-PT. In vivo metabolism of CFZ-PT to CFZ was confirmed in rabbit by HPLC analysis. CFZ concentration in the serum samples taken after oral administration of CFZ-PT(equivalent amount of CFZ) were released and higher than those of CFZ. Oral bioavailability of CFZ-PT was 1.9 fold higher than at of CFZ in rabbits because of enhanced lipophilicity and absorption. Finally, it was concluded that CFZ-PT appears useful as a prodrug of CFZ to improve the oral bioavailability of CFZ.