흰쥐에서의 알파 - 인터페론의 약물체내 속도론적 연구

심창구,김대덕,김현수,정인환,유무영 ( Chang Koo Shim,Dae Duk Kim,Hyun Su Kim,In Whoan Jung,Moo Young Yoo ) 생화학분자생물학회 1987 BMB Reports Vol.20 No.2

Pharmacokinetic behavior of recombinant human interferon alpha (rIFN- α A) was studied in the rat. Serum concentrations of rIFN- α A after intravenous administration could be explained by two - compartment open model. Pharmacokinetic parameters of rIFN- α A administered intravenously at two different doses (9.0 × 10^6 and 3.6 × 10^7 IU/Kg) were calculated by fitting the observed data to the nonlinear least square program. There were no significant differences in pharmacokinetic parameters such as systemic clearance (CLs), apparent distribution volume at steady state (Vd_(ss)), biological half life (t_½) etc. between the two doses. There were also no significant differences between pharmacokinetic parameters of this rIFN- α A and those of Namalva IFN- α which were reported previously by us. rIFN- α A aministered intraveneously had a small distribution volume, which indicates its poor distribution to peripheral or poorly-perfused organs. Renal excretion which might be a sum of filtration, secretion, reabsorption or catabolism in the kidney didn`t show any saturation phenomena in the serum concentration range studied (1 × 10³ - 5 × 10⁴ IU/㎖). Renal clearance accounted less than 0.1% of systemic clearance of rIFN- α A.

연고제로부터 ${\alpha}$-인터페론의 흡수

심창구,김대덕,정인환,김현수,유무영,Shim, Chang-Koo,Kim, Dae-Duk,Jung, In-Whoan,Kim, Hyun-Su,Yoon, Moo-Yung 한국약제학회 1986 Journal of Pharmaceutical Investigation Vol.16 No.3

Time-concentration curves of recombinant human interferon alpha$(rIFN-{\alpha}A)$ in the skin and serum of nude mice or rats were studied after topical application of IFN ointment. IFN appeared in the skin and serum in less than 30 minutes and lasted for more than 10-12 hours at high concentration level after the application to nude mice at a dose of $9.0{\times}10^5\;IU/g$ mouse. But in the rats, IFN was not detected in the serum even 7 hours after the application at a dose of $6.0{\times}10^5\;IU/g$ rat. Topical application of IFN might be useful for the topical and systemic treatment if the human skin resembles that of nude mouse in respect to transport characteristics.

Pharmacokinetic Study of Recombinant Human Interferon Alpha A in Rats

심창구,김대덕,김현수,정인환,유무영,Shim, Chang-Koo,Kim, Dae-Duk,Kim, Hyun-Su,Jung, In-Whoan,Yoo, Moo-Young Korean Society for Biochemistry and Molecular Biol 1987 한국생화학회지 Vol.20 No.2

Recombinant human interferon-${\alpha}A$ (인터페론)를 rat에 정맥주사한 다음의 혈청 및 뇨중 인터페론 역가를 정량하여 약물체내속도론을 이용하여 해석하였다. 정맥주사시 2가지 $9.0{\times}10^6\;IU/ml$ 및 $3.6{\times}10^7\;IU/ml$)로 다른 용량을 투여하여 보았으나 용량에 따른 속도론 파라메타의 유의성있는 차이 (p>0.05)가 나타나지 않았다. 이로부터 이정도의 용량에서는 체내동태에 용량의존성 (포화과정)이 나타나지 않는 것으로 생각되었다. 이 인터페론의 체내동태는 저자 등이 이미 보고한 바 있는 Namalva 인터페론의 체내동태와 유사하였으나 문헌에 있는 베타인터페론과는 상이하였다. 이 인터페론의 뇨중 배설속도와 혈중농도의 상관관계가 직선성을 보이는 점으로부터 비록 인터페론이 신장에서 여파, 분비, 재흡수 및 분해, 대사라는 복잡한 과정을 거쳐 뇨중에 배설된다. 하지만 이 연구에서와 같은 혈중농도 범위내에서는 각 과정에 포화현상이 나타나지 않았다는 (또는 나타나도 무시할 수 있는 정도라는) 사실을 알 수 있었다. 신클리어란스($CL_r$)가 전신클리어란스($CL_s$)의 0.1%에 불과한 것은 인터페론이 신장에서 상당량 catabolism을 받기 때문이라고 생각된다. Pharmacokinetic behavior of recombinant human interferon alpha rIFN-${\alpha}A$ was studied in the rat. Serum concentrations of rIFN-${\alpha}A$ after intravenous administration could be explained by two - compartment open model. Pharmacokinetic parameters of f recombinant human interferon alpha administered intravenously at two different doses $9.0{\times}10^6$ and $3.6{\times}10^7\;IU/kg$) were calculated by fitting the observed data to the nonlinear least square program. There were no significant differences in pharmacokinetic parameters such as systemic clearance (CLs), apparent distribution volume at steady state ($Vd_{ss}$), biological half life ($t_{1/2}$) etc. between the two doses. There were also no significant differences between pharmacokinetic parameters of this rIFN-${\alpha}A$ and those of Namalva rIFN-$\alpha$ which were reported previously by us. rIFN-${\alpha}A$ aministered intraveneously had a small distribution volume, which indicates its poor distribution to peripheral or poorly-perfused organs. Renal excretion which might be a sum of filtration, secretion, reabsorption or catabolism in the kidney didn't show any saturation phenomena in the serum concentration range studied $1{\times}10^3-5{\times}10^4\;IU/ml$). Renal clearance accounted less than 0.1% of systemic clearance of rIFN-${\alpha}A$.

질산우라늄으로 유발시킨 실험적 급성 신장해에 의한 간장의 안티피린 대사 기능 저하

김대덕,심창구,Kim, Dae-Duk,Shim, Chang-Koo 생화학분자생물학회 1988 한국생화학회지 Vol.21 No.1

질산우라늄으로 급성신장장해 (acute renal failure:ARF)를 유발시킨 rat에 안티피린을 IV 또는 경구투여하여 혈청중 농도 추이로 부터 전신클리어란스 ($CL_t$)를 계산하였던바, ARF에 의해 각각의 $CL_t$가 약 40% 저하되는 사실을 발견하였다. 이 원인을 규명하고자 간중량, 위장관흡수, 혈구분배, 혈장단백결합, 간혈류, 간 고유클리어란스 ($CL_{int}$)의 변화를 조사하였다. 그 결과 $CL_t$의 40% 감소는 $CL_{int}$의 감소 (48%)로 잘 설명되었다. $CL_{int}$의 감소 기전에 대해서는 보다 깊은 연구가 필요하겠지만 신장에만 선택적으로 장해를 일으키는 것으로 알려져온 우라늄에 의한 ARF를 신장장해 모델로 사용할 때에는 이와 같은 대사 가능의 저하에 유의하지 않으면 안됨이 밝혀졌다. 이 결과는 신장해시의 간대사 기능이 증가 또는 감소한다는 종래의 논의에 대해 유용한 정보를 제공한 것으로 생각된다. Effect of acute renal failure (ARF) on the hepatic metabolism of antipyrtine was investigated in the rat. Total body clearance $(CL_t)$ of antipyrine was decreased (40%) significantly (P<0.05) by ARF. ARF did not affect the hepatic plasma flow and tissue distribution of antipyrine. The decrease in $CL_t$, was attributed to the decrease in hepatic intrinsic clearance ($CL_{int}$) of antipyrine. Therefore, it seems to be noted that hepatic metabolism of drugs is damaged in some ARF models.

질산우라늄으로 유발시킨 실험적 급성 신장해에 의한 간장의 안티피린의 대사 기능 저하

김대덕,심창구 ( Dae Duk Kim,Chang Koo Shim ) 생화학분자생물학회 1988 BMB Reports Vol.21 No.1

Effect of acute renal failure (ARF) on the hepatic metabolism of antipyrtine was investigated in the rat. Total body clearance (CL_t) of antipyrine was decreased (40%) significantly (p$lt;0.05) by ARF. ARF did not affect the hepatic plasma flow and tissue distribution of antipyrine. The decrease in CL_t was attributed to the decrease in hepatic intrinsic clearance (CL_(int)) of antipyrine. Therefore, it seems to be noted that hepatic metabolism of drugs is damaged in some ARF models.

이중 가교제 또는 알긴산에 의해 물리적인 안정성이 향상된 히알루론산 마이크로입자의 제조

김동환(Dong-Hwan Kim),최애진(Ae-Jin Choi),박충근(Chun-Geon Park),Prabagar Balakrishnan,송충길(Chung Kil Song),심창구(Chang-Koo Shim),김대덕(Dae-Duk Kim),정석재(Suk-Jae Chung) 大韓藥學會 2011 약학회지 Vol.55 No.1

Hyaluronic acid (HA) is a natural polymer consisting of disaccharide units of D-glucuronic acid and N-acetyl- D-glucosamine. It has a great potential and success in cosmetic and biomedical applications. However, native HA is highly soluble and easily metabolized by enzymes such as hyaluronidase. Thus, various studies have been reported on modifying the physicochemical properties of HA, while maintaining its biocompatibility. For controlled drug delivery, many trials for fabricating HA microspheres were achieved under chemical reaction. The HA microspheres fabricated to improve the physical stability of HA using adipic acid dihydrazide (ADH) by cross-linking reaction has been reported earlier, however it lacks the desired physical stability and rapidly decomposes by swelling or enzymes. Therefore, we prepared double cross-linked HA microspheres (DC-HA microspheres) and alginate containing HA microspheres (AC-HA microspheres) to enhance its physicochemical properties. DC-HA microspheres were prepared using trisodium trimetaphosphate (STMP) under crosslinking reaction after ADH cross-linking reaction. AC-HA microspheres were prepared by adding alginate as a networking polymer. These microspheres were characterized by morphology, particle size, zeta potential, stability against hyaluronidase. Results showed that the DC-HA and AC-HA microspheres are more stable than that of HA microspheres.

국산 소나무껍질추출물(파인엑솔^®)을 함유한 제제의 피부흡수 평가

최준호,최민구,한완택,한선정,정석재,심창구,김대덕,Choi, Joon-Ho,Choi, Min-Koo,Han, Ohan-Taek,Han, Sung-Jeong,Chung, Suk-Jae,Shim, Chang-Koo,Kim, Dae-Duk 한국약제학회 2007 Journal of Pharmaceutical Investigation Vol.37 No.6

Pine bark extract is well-known as a very powerful antioxidant, anti-inflammatory, and antibiotic material. French maritime pine bark extract ($Pycnogenol^{(R)}$) of Horphag Research has monopolized the world market over 30 years. Korean red pine bark extract ($Pinexol^{(R)}$) was first manufactured by the patent technology of NutraPharm in Korea in 2006. Feasibility of topical gel and patch formulations of Pinexol was systematically investigated by evaluating the skin absorption of catechin as a reference compound. In vitro hairless mouse skin absorption of catechin from gel formulation was higher than that from patches. However, significant amount of catechin was also deposited inside the skin from patch formulations, which were dependent on the types of pressure sensitive adhesives. Thus, it seems to be feasible to control the topical delivery of Pinexol by using both gel and patch formulations, and be necessary to conduct further systematic investigation.

리포솜 봉입이 로다민 123의 소장 흡수에 미치는 영향

홍순선,이해리,이홍,정석재,김대덕,심창구,Hong, Soon-Sun,Lee, Hae-Ree,Li, Hong,Chung, Suk-Jae,Kim, Dae-Duk,Shim, Chang-Koo 대한약학회 2005 약학회지 Vol.49 No.2

The absorption of a P-gp substrate, rhodamine 123, from a liposomal dosage form was investigated across Caco-2 cell monolayers, rat intestines and rat intestinal Peyer's patches in Ussing chamber, Rhodamine 123 was incorporated into liposomes according to the standard evaporation method, which led to a production of liposomes with a mean diameter of 71.3 nm. The permeability (Papp of rhodamine 123 from a water solution across the monolayer was $2.45{\times}10^{-6}$ cm/s for $A{\leftrightarrow}B$ (apical to basal) and $14.0{\times}10^{-6}$ cm/s for $B{\leftrightarrow}A$ (basal to apical) directions, consistent with the fact that rhodamine 123 is one of the P-gp substrates. The transport of rhodamine 123 from the liposomal dosage form was much lower for both directions compared to the solution of rhodamine 123. The transport of rhodamine 123 across the rat intestine was also significantly decreased for both directions, I.e., influx and efflux, by the liposomal incorporation of the compound. The transport of rhodamine 123 across the Peyer's patch was substantially reduced by liposomal incorporation. No difference was found in the transport between the Peyer's patch and non-Peyer's patch. These observations suggest that the contribution of transport via Peyer's patches in the uptake of liposomes may be minimal, especially for rapidly absorbed compounds like rhodamine 123. Therefore, the increased absorption of P-gp substrates does not appear to be feasible by incorporating the compounds in liposomes, due to negligible involvement of Peyer's patches in the uptake of particulate dosage forms like liposomes. Liposomes may rather represent a sustained release dosage form of incorporated compounds.

Cyclosporin A가 봉입된 nanostructured Lipid carriers의 물리적 특성연구

송충길 ( Chung Kil Song ),정석재 ( Suk Jae Chung ),심창구 ( Chang Koo Shim ),김대덕 ( Dae Duk Kim ) 한국약제학회 2008 Journal of Pharmaceutical Investigation Vol.38 No.1

Differential Changes in Functional Activity of Organic Cation Transporters in Rats with Uranyl Nitrate-Induced Acute Renal Failure

맹한주,정석재,심원식,Sun-Joo Ahn,Sang-Soo Yu,Dae-Duk Kim,심창구 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.8

We studied the impact of experimental kidney failure on the pharmacokinetics of a model organic cation and investigated the underlying mechanism(s) of the organic cation transporters. The systemic pharmacokinetics and tissue distribution of triethylmethylammonium (TEMA), a model organic cation, were characterized after intravenous doses of 0.3-30 μmol/kg in rats with or without uranyl nitrate-induced acute renal failure (UN-ARF). To study the effect of endogenous substrates in plasma from UN-ARF rats on organic cation transport, rOCT- or rOCT2-dependent uptake of tetraethylammonium (TEA) was studied in rOCT1-transfected or rOCT2-transfected LLC-PK1 cells, respectively. As a result, the AUC for TEMA was increased, probably because of decreased total clearance, and the tissue-to-plasma concentration ratio (T/P ratio) of TEMA was unchanged in the liver but decreased significantly in the kidneys of UN-ARF rats. In vitro, the uptake of TEA was decreased significantly by adding UN-ARF plasma, compared with control plasma, in rOCT2-overexpressing LLC-PK1 cells, but not in rOCT1-overexpressing LLC-PK1 cells. These observations suggest that the induction of UN-ARF leads to an accumulation of endogenous organic cation(s), probably rOCT2 substrate(s), in the plasma, thereby affecting the TEMA pharmacokinetics and distribution to the kidneys in rats.