• Biomolecules & Therapeutics
• /
• 제8권1호
• /
• pp.38-43
• /
• 2000

Several studies have shown that the stomach has sufficient alcohol dehydrogenase (ADH) activity to metabolize some amount of orally administered alcohol and the sex-related differences in the first-pass metabolism of alcohol might be associated with differences in the activity of gastric ADH(GADH). The aim of this study was to asses the sex-related differences in GADH in 48 male and 48 female Sprague-Dawley rats aged 1, 4, 10, 15, 20, and 30 weeks which each aged group had same sex ratio. The GADH activity was determined spectrophotometrically at 37$^{\circ}C$. The formation of NADH was monitored at 340nm for 10 minutes in the 1 ml of reaction mixture (0.5 M of Tris-HCl, pH 7.2 + 1.5 M of ethanol + 2.8 mM of NAD + 30 $\mu$l gastric mucosal supernatant). The GADH activity (nM of NADH/min/mg of cytosolic protein) was calculated using molecular extinction coefficient of 6.22 $\textrm{cm}^2$/$\mu$M for NADH. The GADH activities were 2.94$\pm$0.82 (n=48) in female rats and 3.34$\pm$2.17 (n=48) in male rats and had not significant difference between sex. However, the GADH activities were significantly (p<0.01) higher in female (1.91$\pm$0.59 and 3.30$\pm$0.49) than in male (0.68$\pm$0.43 and 1.92$\pm$0.81) of 1 and 4 weeks rats. However, it was significantly (p<0.05) higher in male (6.48$\pm$1.81, 3.65$\pm$1.04 and 5.13$\pm$1.30) than in female (4.23$\pm$1.23, 2.18$\pm$0.77 and 2.56$\pm$0.93) of 10, 20 and 30 weeks rats, respectively. Therefore, the results suggested that sex-related differences of the GADH activities in same aged rats were existed by age.

• Journal of Pharmaceutical Investigation
• /
• 제34권4호
• /
• pp.283-288
• /
• 2004

The pharmacokinetics of nifedipine was studied after oral coadministration of nifedipine (5 mg/kg) with quercetin (1.5, 7.5, 15 and 30 mg/kg, respectively) and 0.5 h or 3days pretreatment with quercetin (1.5 and 7.5mg/kg) in rabbits. Pretreatment of quercetin significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) increased the plasma concentration of nifedipine, but not significant in coadministraiton. The area under the plasma concentration-time curve (AUC) and the peak concentration $(C_{max})$ of nifedipine pretreated with quercetin were increased significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) compared to the control. By coadministration of quercetin, only 7.5 mg/kg of quercetin increased plasma AUC and $C_{max}$ of nifedipine significantly (p<0.05) compared to the control. Plasma AUC of intravenous nifedipine (1 mg/kg) is $4235\;{\pm}\;1192\;ng/ml{\cdot}hr$. Pretreatment of quercetin significantly (p<0.05, at 0.5 h; p<0.01, at 3 days) increased the absolute bioavailability (AB%) of nifedipine to 23.9-29.2% compared to the control (17.8%). Coadministration of quercetin showed no significant effect on the AB% of nifedipine except for 7.5 mg/kg. It is suggested that quercetin alters disposition of nifedipine by inhibition of P-glycoprotein efflux pump and its first-pass metabolism. The dosage of nifedipine should be adjusted when it is administered chronically with quercetin in a clinical situation.

• 한국임상약학회지
• /
• 제23권4호
• /
• pp.316-321
• /
• 2013

Purpose: Atorvastatin, a HMG-CoA reductase inhibitor is widely prescribed in hyperlipidemic patients and telmisartan, an angiotensin receptor blocker is frequently used in the treatment of hypertension. Both drugs are substrates of organic anion transporting polypeptide (OATP) expressed in basolateral membrane in the liver, and undergo high first pass metabolism. Therefore, OATP-mediated hepatic uptake is important for disposition and metabolism of these drugs. The present study was designed to investigate the pharmacokinetic interactions between atorvastatin and telmisartan in rats. Method: Young adult SD rats were divided into three groups (n=6, each) and atorvastatin (10 mg/kg) and telmisartan (4 mg/kg) were orally given alone and together. Heparinized blood was serially taken and plasma concentrations of both drugs were measured using HPLC-MS/MS. Pharmacokinetic parameters of two drugs were calculated. Results: No significant pharmacokinetic change was found except a delay of time to peak of telmisartan when administered with atorvastatin. Each drug at the present dosage seemed to be insufficient to alter the pharmacokinetic parameters of its counterpart drug. Conclusion: Conclusively, co-administration of atorvastatin and telmisartan may lead to negligible clinical consequences.

• Journal of Pharmaceutical Investigation
• /
• 제22권2호
• /
• pp.77-96
• /
• 1992

In recent years intranasal administration of drugs has received great attention as a convenient and efficent method of drug delivery because of its potential to improve the systemic effect of substances with a poor oral bioavailability. In addition to offering advantages such as rapid absorption, fast onset of action and avoiding the first -pass effect, it provides for delivery of drugs from very lipophilic drugs such as steroids to polar and hydrophilic drugs such as peptides and proteins. However, little is still known about the nature of various barriers existing in the nasal mucosae as well as mechanism by which these molecules are absorbed. This review article therefore intends to discuss nasal physiology, experimental methods and evaluation of absorption from the nasal cavity, factors influencing nasal absorption, mechanism of nasal absorption, approaches to improve the residence time and to obtain the sustained-release effect of intranasally administered drugs, promoters and mechanism for the enhancement of nasal absorption, Several examples for intranasal delivery of various systemically effective drugs will be reviewed and illustrated. Drug metabolism in the nasal mucosae and problems associated with intranasal administration of drugs will be also discussed.

• 한국임상약학회지
• /
• 제10권3호
• /
• pp.120-124
• /
• 2000

Diltiazem inhibits calcium channels and leads to vascular smooth muscle relaxation and negative inotroic and chronotropic effects in the heart. Diltiazem (DTZ) is almost completely absorbed after oral administration, but its bioavailability is reduced because of considerable hepatic first-pass metabolism. The main metabolite of DTZ is deacetyldiltiazem. The purpose of this study was to report the pharmacokinetic changes of DTZ and its metabolite, deacetyldiltiazem (DAD) after intravenous administration of diltiazem to control rabbits and rabbits with mild and medium folate-induced renal failure (FIRRs). The area under the plasma concentration-time curves (AUC) of DTZ were significantly increased in mild and medium FIRRs. The metabolite ratio of the DAD to DTZ were significantly decreased in mild and medium FIRRs. The elimination rate constant $(\beta)$ and total body clearances (CLt) of DTZ were significantly decreased in mild and medium FIRRS. These findings suggest that the hepatic metabolism of diltiazem was inhibited and CLt and ${\beta}$ of DTZ were significantly decreased in mild and in rabbits with medium folate-induced renal failure.

• Archives of Pharmacal Research
• /
• 제23권4호
• /
• pp.374-380
• /
• 2000

Propentofylline (PPF, 3-methyl-1-(5-oxohexyl)-7-propylxanthine) has been reported to be a compound for treatment of both vascular dementia and dementia of the Alzheimer type. The short half-life (about 15 min) of PPF at the terminal elimination phase and poor bioavailability after oral administration of PPF to rabbits (Kim et al., 1992) suggest in part that this drug takes the extensive first-pass metabolism in the liver. In addition, the metabolic pathway for PPF remains unclear. The objective of this experiment is to identify urinary metabolites of PPF in rats. For the identification of the metabolites, rat urine was collected after oral administration of 100${m}g/kg$ PPF. PPF metabolite, 3-methyl-1-(5-hydroxyhexyl)-7-propylxanthine, was synthesized and confirmed by gas chromatography/mass spectroscopy (GC/MS) and $^1H$ nuclear magnetic resonance spectroscopy. The urinary metabolites of PPF were extracted with diethyl ether and identified by electron impact and chemical ionization GC/MS. One urinary metabolite was confirmed to be 3-methyl-1-(5-hydroxyhexyl)-7-propylxanthine by synthesized authentic compound. Several metabolites of monohydroxy- and dihydroxy-PPF were identified based on mass fragmentation of both intact and trimethylsilylated derivatives of PPF metabolites and the novel structure of these metabolites is suggested based on mass spectra.

• 약학회지
• /
• 제46권1호
• /
• pp.47-51
• /
• 2002

Although acebutolol (ABT) is almost completely absorbed in the gastrointestinal (Gl) tract, oral bioavailability of the drug is low due to extensive first-pass metabolism in the Gl tract and liver. In the present study, bioavailability and pharmacokinetics of ABT was studied in bile duct-bypassed rabbits after oral administration. For ABT the time to reach the plasma peak (T$_{max}$) and mean resident time (MRT) were increased by the treatment. For diacetolol (DAT), a metabolite of ABT area under the plasma concentration-time curve (AUC), T$_{max}$ and plasma half-life were increased by the treatment. These results indicate that oral bioavailability of ABT is associated with the enterohepatic recycling of bile juice components.nts.

• 약학회지
• /
• 제45권6호
• /
• pp.664-669
• /
• 2001

Acebutolol is almost absorbed after oral administration, but its bioavailability is reduced because of considerable first-pass metabolism through the gastrointestinal tract and liver. The purpose of this study was to report the pharmacokinetic changes of acebutolol (15 mg/kg,oral) and its main metabolite, diacetolol in rabbits pretreated (15 mg/kg, oral) and coadministered (15 mg/kg, S. C., bid for 3 days) with diltiazem. The plasma concentration and area under the plasma concentration-time curves (AUC) of acebutolol and diacetolol were significantly increased in rabbits pretreated and coadministered with diltazem. The elimination rate constant ( $K_{el}$ ) and total body clearances (CL $_{t}$) of acebutolol and diacetolol were significantly decreased and half-life of those were significantly prolonged in the rabbit. Metabolite percentage rate of diacetolol to the plasma concentration of total acebutolol in rabbits pretreated and coadministered with diltiazem were significantly decreased. The results suggest that the dosage of acebutolol should be adjusted when the drug would be administered chronically with diltiazem in a clinical situation.n.

• Investigative Magnetic Resonance Imaging
• /
• 제11권1호
• /
• pp.1-9
• /
• 2007

심장의 영상화에 장애가 되는 요인은 심장 운동, 호흡, 심장 내 혈류 등에 의한 인공물(artifact) 과 심장 조직의 용적이 작음으로 인한 낮은 신호 대 잡음비 등이 있다. 심장 운동에 의한 화질 저하를 막기 위해 신속영상기법(fast imaging technique) 을 이용하여 심장 운동의 특정 위상(phase) 에서만 영상을 얻는 심장동기(cardiac gating) 방법을 이용하고 있다. MRI를 이용한 심장의 검사는 심장의 형태, 심실 기능, 심근 관류, 심근 대사, 관상동맥 영상 등을 대상으로 한다. 심장의 형태적 진단에 있어서 심근내 수분의 정도와 지방조직을 보기 위해 이중(double) 혹은 삼중역전회복기법(triple inversion recovery technique) 을 사용한다. 심근관류검사를 위해서는 조영증강신속경사에코법(contrast-enhanced fast gradient echo technique)을 사용하여 일차통과조영증강(first-pass enhancement) 을 검사한다. 또한 10-15분 지연영상을 얻어 심근내 조영제의 재분포를 검사하여 만성심근경색 등의 심근파괴부위를 확인한다. 심실기능 평가를 위해서는 신속경사에 코법을 이용한 영화영상(cine image) 이 사용되며 심실의 국소적 운동이상 및 심실기능의 정량적 검사가 가능하다. MRI는 관상동맥영상을 제외한 포괄적 심장검사에 실용성이 있다. 특히 지연영상은 다른 검사장비에선 얻을수 없는 유용한 정보이다.

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