Sun H. Lee

Pharmacokinetics and pharmacodynamics of bumetanide after intravenous and oral administration to rats: Absorption from various GI segments

Bumetanide, 2, 8, and 20 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of bumetanide in rats (n=10–12). The absorption of bumetanide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of bumetanide after oral administration were also investigated. After iv dose, the pharmacokinetic parameters of bumetanide, such ast1/2 (21.4, 53.8 vs. 127 min),CL (35.8, 19.1 vs. 13.4 ml/min per kg),CLNR (35.2, 17.8 vs. 12.6 ml/min per kg) andVSS (392, 250 vs. 274 ml/kg) were dose-dependent at the dose range studied. It may be due to the saturable metabolism of bumetanide in rats. After iv dose, 8-hr urine output per 100g body weight increased significantly with increasing doses and it could be due to significantly increased amounts of bumetanide exreted in 8-hr urine with increasing doses. The total amount of sodium and chloride exreted in 8-hr urine per 100g body weight also increased significantly after iv dose of 8 mg/kg, however, the corresponding values for potassium were dose-independent. After oral administration, the percentages of the dose excreted in 24-hr urine as unchanged bumetanide were dose-independent. Bumetanide was absorbed from all regions of GI tract studied and approximately 43.7, 50.0, and 38.4% of the orally administered dose were absorbed between 1 and 24 hr after oral doses of 2, 8, and 20 mg/kg, respectively. Therefore, the appearance of multiple peaks after oral administration could be mainly due to the gastric emptying patterns. The percentages of bumetanide absorbed from GI tract as unchanged bumetanide for up to 24 hr after oral doses of 2, 8, and 20 mg/kg (96.2, 95.4 vs. 98.2%) were not significantly different, suggesting that the problem of precipitation of bumetanide in acidic gastric juices or dissolution may not contribute significantly to the absorption of bumetanide after oral administration. Urine output per 100g body wt increased at oral doses of 8 and 20 mg/kg.

Effect of phenobarbital, 3-methylcholanthrene, and chloramphenicol pretreatment on the pharmacokinetics and pharmacodynamics of azosemide in rats

The effects of pretreatment with the enzyme inducers phenobarbital (PB) and 3‐methylcholanthrene (3‐MC) and the enzyme inhibitor chloramphenicol (CM) on the pharmacokinetic and pharmacodynamic parameters of azosemide were examined after intravenous (IV) administration of azosemide, 10 mg kg−1, to rats. The nonrenal clearance (1·63 versus 3·30 mL min−1 kg−1) of azosemide increased significantly in 3‐MC pretreated rats. This suggested that the nonrenal metabolism of azosemide increased by pretreatment with 3‐MC. This relationship was supported by the significant decrease in 24 h urinary excretion of unchanged azosemide in 3‐MC pretreated rats (54·1 versus 41·1% of IV dose). This relationship was also supported at least in part by the results of a liver homogenate study; the amount of azosemide remaining per gram of liver decreased significantly (48·2 versus 43·0 μg) and the amount of M1 formed increased significantly (4.88 versus 6.66 μg when expressed in terms of azosemide) in 3‐MC pretreated rats after 30 min incubation of 50 μg azosemide in 9000 g supernatant fractions of liver homogenates. The content of hepatic cytochrome P‐450 (0·751 versus 1·57 nmol/mg protein) and the weight of liver (3.53 versus 4·20% of body weight) increased significantly in 3‐MC pretreated rats, suggesting that the metabolizing enzyme(s) for azosemide seemed to be induced by pretreatment with 3‐MC. The 8 h urine output (29·2 versus 18·1 mL) and 8 h urinary excretion of sodium (4·02 versus 2·39 mmol) and chloride (4·01 versus 2·73 mmol) per 100 g body weight decreased significantly in 3‐MC pretreated rats. However, the diuretic, natriuretic, kaluretic, and chloruretic efficiencies were not significantly different between the control and 3‐MC pretreated rats. The pharmacokinetic and pharmacodynamic parameters of azosemide were not significantly different between the control and PB pretreated rats, and similar results were also obtained from the control and CM pretreated rats. The above data indicate that the metabolizing enzyme(s) for azosemide seem(s) to be neither induced by PB pretreatment nor inhibited by CM pretreatment. However, the content of hepatic cytochrome P‐450 and the weight of liver increased significantly in PB pretreated rats, while the values were not significantly different between the control and CM pretreated rats.

Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate-bearing negatively charged liposomes to rats

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (IV) and intramuscular (IM) injection of free MTX (treatment I), freshly prepared MTX-bearing positively charged liposomes (large unilamellar vesicles), PLUVs (treatment II), and empty PLUVs mixed manually with free MTX (treatment III), 4 mg kg-1 as free MTX to rats, using HPLC assay. After 1 min IV infusion, the plasma concentrations of MTX (Cp), the area under the plasma concentration-time curve (AUC, 173 against 314 micrograms mL min-1), the terminal half-life (t1/2, 24.0 against 412 min), the mean residence time (MRT, 13.0 against 324 min), and the apparent volume of distribution at steady state (VSS, 289 against 3370 mL kg-1) were significantly larger, but the total body clearance (CL, 23.1 against 12.8 mL min-1 kg-1), the renal clearance (CLR, 8.38 against 3.09 mL min-1 kg-1), the non-renal clearance (CLNR, 14.6 against 9.56 mL min-1 kg-1), and the amount of MTX excreted in urine (Xu, 415 against 275 micrograms) were significantly lower in treatment II than in treatment I. This could be due to the fact that some of the MTX-bearing PLUVs were entrapped in tissues and the rest were present in plasma (larger MRT and Vss in treatment II), and MTX is slowly released from MTX-bearing PLUVs (longer t1/2 in treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX in MTX-bearing PLUVs (larger Cp and AUC and slower CL in treatment II). Saturable formation of 7-hydroxymethotrexate from MTX was reported in rabbit blood and nonlinear disposition of MTX was also reported in rats and rabbits (lower Xu and CLR in treatment II). After 1 min IV infusion, some pharmacokinetic parameters of MTX, such as AUC, CL, CLR, CLNR, and Xu, were significantly different between treatments I and III, but nonetheless the differences were smaller than those between treatments I and II. After both IV and IM administration, the amount of MTX remaining per gram of tissue or organ in the kidney, stomach, small intestine, and large intestine was significantly smaller in treatment II than in treatment I.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of methotrexate after intravenous and intramuscular injection of methotrexate‐bearing neutral liposomes to rats

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) and intramuscular (i.m.) injection of free MTX (treatment I), MTX‐bearing neutral liposomes (large unilamellar vesicles), OLUVs (treatment II) and free MTX mixed manually with empty OLUVs (treatment HI), 4 mg/kg as free MTX to rats. After i.v. infusion in 1 min, the plasma concentrations of MTX (Cp), area under the plasma concentration‐time curve (AUC, 173 vs. 1110 μg ml/min), terminal half‐life (t1/2, 24.0 min vs. not determined), mean residence time (MRT, 13.0 vs. 165 min) and apparent volume of distribution at steady state (Vss 289 vs. 584 ml/kg) increased significantly; however, total body clearance (CI, 23.1 vs. 3.61 ml/min/kg), renal clearance (ClR, 8.38 vs. 1.88 ml/min/kg) and nonrenal clearance (ClNR, 14.6 vs. 1.66 ml/min/kg) decreased significantly from treatment II when compared with the values from treatment I. This could be due to the fact that some of the MTX‐bearing OLUVs were entrapped in tissues and the others were present in plasma (increase in MRT and Vss from treatment II). MTX was slowly released from the MTX‐bearing OLUVs (increase in t1/2 from treatment II). With the present HPLC assay, the concentrations of MTX represent the sum of the free MTX and MTX in MTX‐bearing OLUVs (increase in Cp and AUC, and decrease in CI from treatment II). Some pharmacokinetic parameters of MTX, such as t1/2 (24.0 vs. 58.2 min), MRT (13.0 vs. 23.3 min) and Vss (289 vs. 456 ml/kg) were significantly different after i.v. administration of empty OLUVs (between treatments I and III); however, the differences seemed to be smaller than those between treatments I and II. After i.m. administration, t1/2 (37.2 min vs. not determined) and the total amounts of MTX excreted in urine (Xu, 319 vs. 171 μg) were significantly different after treatments I and II. After both i.v. and i.m. administration, the amount of MTX remaining per gram of tissue, and/or tissue to plasma ratio (T/P) of MTX were significantly reduced in the kidney, small intestine, large intestine or stomach from treatment II when compared with those from treatment I. This implies that the side‐effects of MTX on the kidney and gastrointestinal tract could be reduced after i.v. or i.m. administration of MTX‐bearing OLUVs rather than free MTX. The mean encapsulation efficiency of MTX in MTX‐bearing OLUVs was 3.88% and the MTX was released slowly from MTX‐bearing OLUVs when incubated in phosphate‐buffered saline, rat plasma and rat liver homogenate.

Dose-dependent pharmacokinetics of human granulocyte/macrophage colony-stimulating factor in rabbits

Abstract The pharmacokinetic parameters of HGM-CSF, such as t 1 2 (11.3, 10.4, 39.2, 39.2 vs 51.6 min), MRT (11.6, 10.9, 22.9, 20.3 vs 18.3 min), CL (25.0, 21.1, 6.98, 7.94 vs 6.51 ml min −1 kg −1 ), cl NR (24.6, 19.9, 6.87, 6.92 vs 4.24 ml min −1 kg −1 ) and V ss (292, 211, 162, 162 vs 120 ml kg −1 ) were dose-dependent after intravenous administration of the factor to rabbits at the doses of 0.05, 0.1, 0.5, 1.0 and 2.5 mg kg −1 , respectively: The dose-dependent pharmacokinetics of HGM-CSF in rabbits appeared to represent saturable metabolism of the factor at the dose ranges studied. HGM-CSF was highly concentrated in the kidney and liver, and less concentrated in other tissues or organs studied at 2 h after subcutaneous administration of the factor, 0.5 mg kg −1 to rabbits.

Dose-independent pharmacokinetics of recombinant human interferon-αA in rabbits

The pharmacokinetic parameters of rHuIFN-α A, such as t12(53.7–85.3 min), MRT (29.5–42.4 min), Vss (107–163 ml kg−1) and CL (3.65–4.69 ml min−1 kg−1) were found to be dose-independent after intravenous administration to rabbits using a 1000-fold range of doses, i.e., 106–109 U kg−1. The extent of bioavailability was essentially complete when interferon at 107 U kg−1 was administered subcutaneously to rabbits. Radioactivity was highly concentrated in the kidney and plasma, and less concentrated in the other tissues or organs studied at 2 h after subcutaneous administration of the radiolabelled interferon, 125I-rHuIFN-α A (100000 cpm kg−1) to rabbits.

Pharmacokinetics of ciprofloxacin after intravenous administration of ciprofloxacin-TOF in rabbits

Abstract The pharmacokinetic parameters and tissue distribution of ciprofloxacin were compared after intravenous (i.v.) administration of ciprofloxacin-HCl or ciprofloxacin-TOF salts, 30 mg kg −1 as free ciprofloxacin to rabbits. The pharmacokinetic parameters and tissue distribution of ciprofloxacin were not significantly different between i.v. administration of ciprofloxacin-TOF and ciprofloxacin-HCl salts, indicating that ciprofloxacin-TOF salt is pharmacokinetically equivalent to ciprofloxacin-HCl salt. Radioactivity was evenly distributed in all the tissues (or organs) studied at 48 h after i.v. administration of 1- 14 C- or 1,2,3,4,5- 14 C-labelled TOF, 750000 dpm kg −1 to rabbits and the mean percentages of i.v. dose excreted in 48 h urine as measured radioactivity were 23.6 and 26.1% for [1- 14 C]- and [1,2,3,4,5- 14 C]TOF, respectively.