• The Korean Journal of Pharmacology
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• v.26 no.1
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• pp.83-90
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• 1990

The effect of cimetidine on theophylline metabolism was examined in dogs. Single dose intravenous theophylline kinetic studies were performed in cross-over manner before and after one week intravenous cimetidine (30 mg/kg/day) treatment. Cimetidine decreased theophylline clearance by an average of 31% (p<0.05) and prolonged theophylline half-li fe by an average of 29% (p<0.01) compared to those in control peirods. However, steady-state volume of distribution and protein binding of theophylline were not changed significantly. Twenty-four hours urinary excretion of 3-methylxanthine, 1-methyluric acid and 1,3-dimethyluric acid, which are the major metabolites of theophylline, were all decreased after cimetidine treatment, whereas the excreted fractions of individual metabolites were unchanged by cimetidine. From the above data, it could be susggested that cimetidine decreases theophylline clearance and prolongs the half-life by non-specific inhibition of the demethylations and 8-hydroxylation pathways.

• Archives of Pharmacal Research
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• v.27 no.2
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• pp.254-258
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• 2004

The purpose of this study was to investigate the pharmacokinetic alteration of diltiazem and its main metabolite, deacetyldiltiazem, after oral administration of diltiazem in rabbits with or with-out cimetidine co-administration. The area under the plasma concentration-time curve (AUC) of diltiazem was significantly elevated in rabbits pretreated with cimetidine, suggesting that the oral clearance, an index of intrinsic clearance, may be decreased by the cimetidine treatment. Consistent with the increased AUC by the treatment, peak plasma concentration ($C_{max}$) for diltiazem was also elevated. Apparent volume of distribution normalized by the bioavailability (($V_{d}$/F) of diltiazem increased sigrificantly in rabbits pretreated with cimetidine increased. Taken together with the fact that the first pass metabolism for diltiazem is the primary determinant for the oral bioavailability, these observations indicate that increases in the oral clearance and (($V_{d}$/F may be a manifestation of the decreased first pass metabolism. Consistent with the hypothesis, the AUC of deacetyldiltiazem was significantly decreased in rabbits with cimetidine treatment. Ratio of deacetyldiltiazem to total diltiazem in the plasma was significantly decreased in rabbits with cimetidine treatment. These observations suggested that the metabolism of diltiazem to deacetyldiltiazem was reduced by cimetidine treatment and that the dosage of diltiazem should be adjusted when the drug is co-administered chronically with cimetidine in a clinical setting.

• YAKHAK HOEJI
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• v.32 no.5
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• pp.319-327
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• 1988

Pharmacokinetic interaction of cimetidine and isoniazid was investigated in the rabbits. Isoniazid was administered orally at a dose of 30mg/kg to six rabbits after 10, 20, and 30mg/kg pretreatment of cimetidine twice a day for 10days. Concentration of the free and the total isoniazid in the blood and the urine was determined by spectrophotometer. Relative bioavailability and biological half-life($t\frac{1}{2}{\beta}$) were increased significantly by cimetidine pretreatment. Overall elimination rate constant and total clearance of isoniazid were decreased significantly by cimetidine pretreatment. The ratio of metabolites to isoniazid in the blood and the urine was decreased significantly by cimetidine pretreatment. Relative bioavailability, INAH to metabolites ratio in the blood and decrease in total clearance were highly correlated with the does of cimetidine pretreated. This result might be due to the inhibition of isoniazid metabolism in the liver by cimetidine pretreatment.

• Korean Journal of Clinical Pharmacy
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• v.7 no.2
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• pp.51-63
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• 1997

The effect of cimetidine administration on the pharmacokinetic parameters of cyclosporine were determined in healthy voluteers. This study was performed in 10 volunteers of age ranged 22-48 years and body weight 48-62 kg. This study was performed with cross-over design. Mono cyclosporine and cyclosporine metabolites was extracted from whole blood analysed by fluororescence polarization immune assay (TDX-FLX, Abbott). After coadministration of cimetidine (300 mg) with cyclosporine (300 mg) orally, maximum concentration of mono cyclosporine was significantly increased $1221{\pm}143\;ng/ml\;to\;1562{\pm}184\;ng/ml$ (P<0.05), area under the time curve of cyclosporine (12 hr) also was significantly increased $7478{\pm}829\;ng/ml{\cdot}hr\;to\;9721{\pm}879\;ng/ml{\cdot}hr$ (P<0.05) and absolute baioavailability of cyclosporine was increased $50\pm5.6\%\;to\;57.6\pm6.1\%\;(P<0.05)$ compared to control group. The blood concentrations of cyclopsorine metabolites were significantly decrased (P<0.05) after coadministration of cimetidine. In cimetidine pretreated group, blood mono cyclosporine concentrations were increased significan시y $1220.0\pm203.00\;ng/ml\;to\;1510.0\pm204.00\;ng/ml$ compared with control group (P<0.05). In the mono cyclosporine pharmacokinetic parameter after oral administration absorption rate and maximum concentration were significantly higher in cimetidine coadministered and pretreated group than control group (P<0.05). The ratio of metabolites and mono cyclosporine concentrations was decreased significantly from $70.8\%\;in\;control\;to\;34.8\%$ in coadministration of cimetidine orally. As matter of facts these reults are considered to inhibition of cyclosporine hepatic metabolism and increasing of cyclosporine absorption rate in gastrointestinal tract because of maintaining cyclosporine stability in elevated gastric pH by cimetidine. We considered, it appeares that cimetidine increase bioavailability of cyclosporine by increasing oral absorption and by decreasing hepatic clearance. But the absorption and clearance of cyclosporine was highly variable individually, and therefore we consider that cyclosporine blood level monitoring would be essential in patients with cimetidine co-administration.

• YAKHAK HOEJI
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• v.48 no.5
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• pp.297-302
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• 2004

The purpose of the present study was to evaluate the bioequivalence of two cimetidine tablets, Tagamet (Yuhan Pharm. Co., Ltd.) and Nex (Bi-nex Pharm. Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). The cimetidine release from the two cimetidine tablets in vitro was tested using KP Apparatus I method with various dissolution media (pH 1.2, 4.0, 6.8 buffer solutions and water). The dissolution profiles of two cimetidine tablets were very similar at all dissolution media. Twenty four healthy male volunteers were divided into two groups with a randomized $2{\times}2$ cross-over study. After four tablets (800 mg cimetidine) were orally administrated, blood was taken and the concentrations of cimetidine in serum were determined using HPLC with UV detector. The pharmacokinetic parameters such as $AUC_{t}$, $C_{max}$ and $T_{max}$ were determined. The result showed that the differences in $AUC_{t}$, and $C_{max}$ between two cimetidine tablets based on the Tagamet were -6.82% and -12.98%, respectively. There were no sequence effects between two tablets in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log(0.8) to log(1.25) (e.g., log(0.90)log(0.97) and log(0.82)log(0.93) for $AUC_{t}$ and $C_{max}$, respectively), indicating that Thrumetin tablet was bioequivalent to Tagamet tablet.

• Korean Journal of Clinical Pharmacy
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• v.3 no.2
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• pp.163-168
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• 1993

The influence of cimetidine pretreatment(100mg/kg, single i.p.) on the hepatic blood flow was investigated using pharmacokinetic parameters of indocyanine green(ICG) in the rat on the basis of hepacc perfusion-limited model. ICG(1mg/kg) was respectively administered via femoral and portal vein to the control and to the cimetidine-pretreated rats. The rate constant K12, K20 and the systemic clearance(CLt) of ICG were significantly(p<0.05) decreased ill the cimetidine-pretrea-to(B rats, but no significant diffirences were observed in hematocrit and liver weight. The biliary excretion rates of ICG were also decreased regardless of the route of administration in the cimetidine-pretreated rats. And also the hepatic blood flow in rats was decreased about $16\%$ by cimetidine. It may be concluded that the decreased hepatic blood flow with cimetidine mainly contributed to the decreased hepatic uptake and the decreased systemic clearance of ICG.

• YAKHAK HOEJI
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• v.29 no.6
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• pp.362-366
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• 1985

These paper was attempted to investigate the mechanism of increased blood level of sulfisomidine by cimetidine pretreatment pharmacokinetically. Especially, effect of cimetidine pretreatment on both renal clearance and biliary clearance of sulfisomidine was studied in rabbits. The results are as follows. The blood level of sulfisomidine administered intravenously in dose of 25mg/kg was elevated significantly by cimetidine pretreatment. Relative bioavailability and biological half-life were increased significantly by cimetidine pretreatment. Overall elimination rate constant ($betha$) and distribution rate constant ($K_{13}$) of sulfisomidine were decreased significantly by cimetidine pretreatment. The renal and biliary clearance of sulfisomidine were decreased significantly compared with those of control rabbits by cimetidine pretreatment. The results may be also related to the inhibition of sulfisomidine metabolism enzyme activity or reduction of blood flow in the liver.

• Fisheries and Aquatic Sciences
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• v.5 no.1
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• pp.28-31
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• 2002

Effects of cimetidine, a cytochrome P450 inhibitor, on the benzo[a]pyrene (BaP)-mediated cytochrome P450 induction and lipid peroxidation of liver in olive flounder, Paralichthys olivaceus, were investigated. Fish were fed either a cimetidine-supplemented diet or a cimetidine-free control diet once daily to satiation for 3 days. After 6 hrs of last feeding, the fish received intraperitoneal (i.p.) injection of BaP (20 mg/kg of body weight) dissolved in sterile corn oil $(100 \mu L)$ or received only a corn oil i.p. injection. At 1, 2, 3, and 7 days after the injection, hepatic cytochrome P450 and thiobarbituric acid reactive substances (TBARS), an indicator of lipid peroxidation, were analyzed. BaP injection resulted in an increase of hepatic cytochrome P450, and the fish fed the cimetidine-supplemented diet before injection of BaP showed delayed increase of hepatic cytochrome P450 compared to the fish fed a cimetidine-free diet and BaP injected. Injection of BaP clearly induced hepatic lipid peroxidation, and consistently higher TBAR values were shown in the fish fed a cimetidine­supplemented diet before injection of BaP than the fish injected with BaP alone.

• Biomolecules & Therapeutics
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• v.15 no.2
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• pp.102-107
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• 2007

Cimetidine, a substrate for P-glycoprotein (P-gp), is a well known drug interacting with a variety of drugs and results in alteration of pharmacokinetic parameters by concomitant administration. The aim of present study was to investigate whether cimetidine affects the transport of various quinolone antibiotics in human colorectal cancer cell line (Caco-2) system which has been typically used to investigate drug transport via P-gp. The apparent permeability coefficients (P$_{app}$) value of 9 quinolone antibiotics in the co-treatment with cimetidine was examined. Apical to basolateral (AP-to-BL) transport of fleroxacin in the co-treatment with cimetidine was increased to 1.5-fold (p<0.01) compared with that of fleroxacin alone, whereas basolateral to apical (BL-to-AP) transport of fleroxacin was decreased to 0.83-fold significantly (p<0.05). Ofloxacin was decreased to 0.8-fold (p<0.01) and 0.72-fold (p<0.01) significantly in AP-to-BL and BL-to-AP direction, respectively by cimetidine cotreatment. The P$_{app}$ values of gatifloxacin, moxifloxacin, ciprofloxacin and rufloxacin also were changed by cimetidine. These results have a potential that cimetidine influences on the pharmacokinetics of quinolone antibiotics. It suggests that careful drug monitoring and dosage adjustment may be necessary during the co-administration of quinolone antibiotics with cimetidine.

• Journal of Pharmaceutical Investigation
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• v.32 no.3
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• pp.209-213
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• 2002

Diltiazem inhibits calcium channels and Iεads to vascular smooth muscle rεlaxation and negative inotropic and chronotropic effects in the hεart. Diltiazem is almost completely absorbεd after oral administration, but its extent of absolute oral bioavailability is reduced because of considerable first-pass hepatic metabolism. Diltiazem is able to dilate renal vasculature and can increase the glomerular filtration rate and renal sodium excretion. The purpose of this study was to report the pharmacokinetic changes of diltiazem after oral administration of diltiazem, 20 mg/kg, in rabbits coadministered with cimetidine, 20 mg/kg and pretreated twice per day for 3 days at cimetidine dose of 20 mg/kg. The area under the plasma concentration-time curve (AUC) of diltiazem was significantly higher in rabbits pretreated with cimetidine than that in control rabbits (p<0.01), showing about 149% increased relative bioavailability. The peak plasma concentration $(C_{max})$ and elimination half-life of diltiazem were increased significantly (p<0.05) in rabbits pretreated with cimetidine compared with those in control rabbits. This findings could be due to significant reduction of elimination rate constant by pretreated with cimetidine. The effects of cimetidine on the pharmacokinetics of oral diltiazem were more considerable in rabbits pretreated with cimetidine compared with those in control rabbits. The results suggest that the dosage of diltiazem should be adjusted when the drug would be co-administerεd chronically with cimetidine in a clinical situation.