Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant Nagase analbuminemic rats: importance of globulin binding for the pharmacodynamic effects.

The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, bumetanide, could be expected in analbuminemic rats if plasma protein binding of bumetanide is considerable in the rats. This was proved by this study. After intravenous administration of bumetanide, 10 mg/kg, to analbuminemic rats, the plasma protein binding of bumetanide was 36.8% in the rats mainly due to considerable binding to alpha- and beta-globulins (this value, 36.8%, was considerably greater than only 12% for furosemide), and hence the percentages of intravenous dose of bumetanide excreted in 6 h urine as unchanged drug was 16.0% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of bumetanide to analbuminemic rats, the area under the plasma concentration-time curve from time zero to time infinity (1012 compared with 2472 microg min/mL) was significantly smaller [due to significantly faster both renal clearance (1.49 compared with 0.275 ml/min/kg) and nonrenal clearance (8.30 compared with 3.71 ml/min/kg)], terminal half-life (9.94 compared with 22.4 min) and mean residence time (4.25 compared with 5.90 min) were significantly shorter (due to faster total body clearance, 9.88 compared with 4.05 ml/min/kg), and amount of 6 h urinary excretion of unchanged bumetanide (559 compared with 261 microg, due to increase in intrinsic renal excretion) was significantly greater than that in control rats. The 6 h urine output and 6 h urinary excretions of sodium, chloride and potassium were comparable between two groups of rats although the 6 h urinary excretion of bumetanide was significantly greater in analbuminemic rats. This could be explained by the following. The amount of urinary excretion of bumetanide was significantly greater in analbuminemic rats than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rates of bumetanide during 0-30 min reached a upper plateau with respect to urine flow rate as well urinary excretion rates of sodium, potassium and chloride, therefore, the diuretic effects (6 h urine output and 6 h urinary excretions of sodium, potassium and chloride) were not significantly different between two groups of rats.     

Pharmacokinetics of intravenous methotrexate in mutant Nagase analbuminemic rats

It has been reported that the plasma (or serum) levels of albumin and globulins were lower and higher, respectively, than the serum levels in control rats. Hence, it could be expected that these changes could affect the renal clearance (Cl(r)) of methotrexate in Nagase analbuminemic rats (NARs) due to changes in plasma protein binding values. Therefore, methotrexate at a dose of 100 mg/kg was administered intravenously to control rats and NARs. The plasma protein binding of methotrexate in NARs was significantly greater (29.4% increase) than the controls, probably due to the considerable binding of the drug (34.2%) to 1.8% beta-plus 0.63% gamma-globulins. The Cl(r) of methotrexate in NARs was significantly slower (36.1% decrease) than the controls, due to the significantly smaller Ae(0-24h) (25.8% decrease). The smaller Ae(0-24h) could be due to the significantly smaller free (unbound to plasma proteins) fractions of methotrexate in plasma (13.8% decrease) in NARs, since methotrexate was mainly excreted in the urine via glomerular filtration. However, the Cl(nr) values were comparable between the control rats and NARs. This could be because methotrexate is not metabolized considerably via hepatic CYP isozymes based on control rats pretreated with SKF 525-A (a nonspecific inhibitor of hepatic CYP isozymes in rats).     

Pharmacokinetics of 5-fluorouracil in mutant Nagase analbuminemic rats: faster metabolism of 5-fluorouracil via CYP1A

It has been reported that plasma albumin concentrations were significantly lower in cancer patients than those in the healthy volunteers, and the expression and mRNA level of hepatic microsomal cytochrome P450 (CYP) 1A2 increased in mutant Nagase analbuminemic rats (NARs). After intravenous administration of 5-fluorouracil at a dose of 30 mg/kg to NARs, the time-averaged nonrenal clearance (Clnr) of the drug was significantly faster than the controls (51.3 versus 28.8 ml/min/kg), possibly due to an increase in the expression and mRNA level of CYP1A2 in NARs. In order to determine whether 5-fluorouracil is metabolized via CYP1A2 in male Sprague-Dawley rats, the rats were pretreated with 3-methylcholanthrene (a main inducer of CYP1A1/2 in rats). The Clnr of 5-fluorouracil was significantly faster (34.3 versus 27.3 ml/min/kg) in rats pretreated with 3-methylcholanthrene. The aforementioned data indicate that CYP1A is involved in the metabolism of 5-fluorouracil in rats.     

Pharmacokinetics and pharmacodynamics of intravenous torasemide in diabetic rats induced by alloxan or streptozotocin

The pharmacokinetic and pharmacodynamic parameters of torasemide were compared after intravenous administration at a dose of 2 mg/kg to diabetic rats induced by alloxan (DMIA) or streptozotocin (DMIS), and their respective control rats. It was reported that torasemide was mainly metabolized via CYP2C11 in rats and the expression and mRNA level of CYP2C11 decreased in DMIA and DMIS rats. Hence, it could be expected that the time-averaged nonrenal clearance (Cl(nr)) of torasemide could be slower in the diabetic rats. As expected, the Cl(nr) values were significantly slower in DMIA (0.983 versus 1.35 ml/min/kg) and DMIS (0.998 versus 1.36 ml/min/kg) rats. However, the time-averaged renal clearance (Cl(r)) values of torasemide were significantly faster in DMIA (0.164 versus 0.0846 ml/min/kg) and DMIS (0.205 versus 0.0967 ml/min/kg) rats due to urine flow rate-dependent timed-interval Cl(r) of torasemide in rats. The comparable time-averaged total body clearance (Cl) values between the diabetic and control rats were due to partially compensated Cl(r) in the diabetic rats. The 8 h urine output and diuretic efficiency increased significantly in the diabetic rats due to significantly greater 8 h urinary excretion of unchanged torasemide and at least partly due to an increase in urine output in diabetes per se (without administration of any drugs).     

Pharmacokinetics and pharmacodynamics of intravenous azosemide in mutant Nagase analbuminemic rats.

This paper reports 1) the increase in expression of CYP1A2 in mutant Nagase analbuminemic rats (NARs), 2) the role of globulin binding of azosemide in circulating blood in its urinary excretion and hence its diuretic effects in NARs, and 3) the significantly faster renal (CL(R)) and nonrenal (CL(NR)) clearances of azosemide in NARs. Azosemide (mainly metabolized via CYP1A2 in rats), 10 mg/kg, was intravenously administered to control rats and NARs. Northern and Western blot analyses revealed that the expression of CYP1A2 increased approximately 3.5-fold in NARs as compared with control. The plasma protein binding of azosemide in control rats and NARs was 97.9 and 84.6%, respectively. In NARs, plasma protein binding (84.6%) was due to binding to alpha- (82.6%) and beta- (68.9%) globulins. In NARs, the amount of unchanged azosemide excreted in 8-h urine was significantly greater (37.7 versus 21.0% of intravenous dose) than that in control rats due to an increase in intrinsic renal active secretion of azosemide. Accordingly, the 8-h urine output was significantly greater in NARs. The area under the plasma concentration-time curve of azosemide was significantly smaller (505 versus 2790 microg. min/ml) in NARs because of markedly faster CL(R) (7.36 versus 0.772 ml/min/kg, secondary to a significant increase in urinary excretion of azosemide and intrinsic renal active secretion). Additionally, CL(NR) was significantly faster (12.4 versus 3.05 ml/min/kg, because of approximately 3.5 fold increase in CYP1A2) in NARs compared with control. Based on in vitro hepatic microsomal studies, the intrinsic M1 [a metabolite of azosemide; 5-(2-amino-4-chloro-5-sulfamoylphenyl)-tetrazole] formation clearance was significantly faster (67.0% increase) in NARs than that in control rats, and this supports significantly faster CL(NR) in NARs. Renal sensitivity to azosemide was significantly greater in NARs than in control rats with respect to 8-h urine output (385 versus 221 ml/kg) and 8-h urinary excretions of sodium, potassium, and chloride. This study supports that in NARs, binding of azosemide to alpha- and beta-globulins in circulating blood play an important role in its diuretic effects.     

Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein binding

It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Cl_nr was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first‐pass effect in NARs than in the controls. Copyright © 2009 John Wiley & Sons, Ltd.     

Pharmacokinetics of TDP223206 following intravenous and oral administration to intact rats and intravenous administration to bile duct-cannulated rats

The pharmacokinetics of TDP223206 was studied following single intravenous and oral administrations in rats. A mixture of TDP223206 and (14)C-TDP223206 were administered to intact and bile duct-cannulated rats. Following intravenous administration, plasma concentrations declined biphasically. The AUC(inf) increased linearly with dose but was not dose proportional. The PK parameters of TDP223206 indicated low clearance (254-386 ml/h/kg) and a moderate volume of distribution (968-1883 ml/kg). The bioavailability was 32.95% and 24.46% for 10 and 50 mg/kg oral doses, respectively. (14)C-TDP223206 was distributed widely into different tissues with small intestine, liver, kidneys and large intestine having large tissue to plasma ratios. (14)C-TDP223206 was the major circulating component in the plasma. A total of 91.2% of administered radioactivity of (14)C-TDP223206 was recovered in bile indicating that biliary excretion was the major pathway for drug elimination. (14)C-TDP223206-acyl glucuronides were the major metabolites in bile. The oxo-(14)C-TDP223206 was the major metabolite in plasma and an important metabolite in bile. Two forms of diastereomeric acyl glucuronides of (14)C-TDP223206 were detected in bile with similar LC/MS intensities suggesting a similar biotransformation capacity. Only one form of these (14)C-TDP223206-acyl glucuronides was detected in plasma suggesting that enterohepatic recirculation was related to the nature of the stereo-isomers.     

Pharmacokinetics of intravenous chlorzoxazone in rats with dehydration and rehydration: effects of food intakes

The following results were obtained recently from our laboratories; in rats with 72-h water deprivation (rats with dehydration), the hepatic cytochrome P450 2E1 (CYP2E1) was three-fold induced with an increase in the mRNA. Rehydration of 48-h water-deprived rats for the next 24 h with free access of food (rats with rehydration) restored CYP2E1 level to that of control. However, rehydration of 48-h water-deprived rats for the next 24 h with limited food supply (20% of control) failed to restore the CYP2E1 level to that of control. Hence, the CYP2E1 changes in rats with dehydration and rehydration resulted from differences in food intakes but not from dehydration or rehydration per'se. Chlorzoxazone (CZX) is metabolized to 6-hydroxychlorzoxazone (OH-CZX) mainly by CYP2E1 in rats. Therefore, the pharmacokinetics of CZX and OH-CZX were compared after intravenous administration of CZX, 25 mg/kg, to control rats and rats with dehydration and rehydration with free access of food. In rats with dehydration, the amount of 24-h urinary excretion of free OH-CZX plus its glucuronide conjugates (Ae (OH-CZX, 0-24 h,) expressed in terms of intravenous dose of CZX) was significantly greater (45.6 compared with 35.6%) and area under the plasma concentration-time curve from time zero to time infinity (AUC) of CZX was significantly smaller (2190 compared with 3200 micro g min/ml) than those in control rats. The above data indicated that the formation of OH-CZX increased significantly in rats with dehydration due to 3-fold induction of CYP2E1. In rats with rehydration with free access of food, the Ae (OH-CZX, 0-24 h) (39.0 compared with 35.6%) and AUC of CZX (2870 compared with 3200 micro g min/ml) were restored (comparable) to control levels since the expression of CYP2E1 in rats with dehydration returned to control level by rehydration. The above data indicate that CZX could be used as a chemical probe to assess the activity of CYP2E1 in rats with dehydration and rehydration.     

Pharmacokinetics and pharmacodynamics of furosemide after intravenous and oral administration to spontaneously hypertensive rats and DOCA-salt-induced hypertensive rats

The pharmacokinetics and pharmacodynamics of furosemide were investigated after intravenous (i.v.), 1 mg/100 g body weight, and oral administration, 2 mg per 100g body weight, to spontaneously hypertensive rats (SHRs) and deoxycorticosterone acetate-salt-induced hypertensive rats (DOCA-salt rats). After i.v. administration, the 8 h urinary excretion of furosemide/g kidney (397 versus 572 μg) was significantly lower and the non-renal clearance (5.78 versus 3·94 ml min^?1 kg^?1) was significantly faster in SHRs of 16 weeks of age than in age-matched control Wistar rats. This suggested that the nonrenal metabolism of furosemide could be faster in SHRs of 16 weeks of age than in age-matched control Wistar rats, and this could be supported by the significantly greater amount of 4-chloro-5-sulphamoyl anthranilic acid, a metabolite of furosemide, excreted in 8 h urine as expressed in terms of furosemide (11·1 versus 4·79% of the i.v. dose) in SHRs. It could also be supported at least in part by a study of liver homogenate; the amount of furosemide remaining per gram of liver after 30 min incubation of 50μg of furosemide with the 9000g supernatant fraction of liver homogenate was significantly smaller (40·4 versus 43·7μg) in SHRs of 16 weeks of age than in age-matched Wistar rats. The greater metabolic activity of furosemide in liver may also be supported by the result that the amount of hepatic cytochrome P-450 (0·7013 versus 0·5186 nmol/mg protein) and the weights of liver (3·52 versus 2·93% of body weight) were significantly greater in SHRs of 16 weeks of age than in age-matched Wistar rats. After i.v. administration of furosemide, the 8 h urine output (9·93 versus 16·5 ml) and 8 h urinary excretion of sodium (1·21 versus 2·05 mmol) and chloride (1·37 versus 2·17 mmol) per gram of kidney in SHRs of 16 weeks of age were lower than those in age-matched Wistar rats, this could be due to the significantly smaller amount of furosemide excreted in 8 h urine per gram of kidney. After oral administration, the pharmacokinetics and pharmacodynamics of furosemide were not significantly different between SHRs and the control Wistar rats of 16 weeks of age. After i.v. and oral administration of furosemide, there were no significant differences in the pharmacokinetics and pharmacodynamics between DOCA-salt rats and control SD rats of 16 weeks of age except for the significantly lower urinary excretion of potassium per gram of kidney in DOCA-salt rats. On the other hand, the 8 h urinary excretion of furosemide and non-renal clearance were not significantly different between SHRs of six weeks of age and age-matched control Wistar rats after i.v. administration of furosemide. Since the non-renal metabolism of furosemide was not faster in either DOCA-salt rats of 16 weeks of age or SHRs of six weeks of age than that in the respective age-matched control group, the faster non-renal metabolism of furosemide in SHRs of 16 weeks of age could be due to the physiological factor from the chronic phase of hypertension in SHRs, and could not be due solely to the heredity of SHRs or the hypertensive state itself.     

Pharmacokinetics of omeprazole in rats with water deprivation for 72 hours

Dehydration can occur by excessive sweating, polyuria, severe diarrhea and hyperthermia. Previous studies reported that the expressions of CYP1A1/2 and 3A1(23)/2 were not changed in male Sprague-Dawley rats with 72 h water deprivation (dehydrated rats), and that the metabolism of omeprazole is mainly catalysed via CYP1A1/2, 2D1 and 3A23/2 in rats. Hence, it could be expected that the hepatic metabolism of omeprazole would not be changed considerably in dehydrated rats, if the contribution of CYP2D1 to the metabolism of omeprazole in dehydrated rats is not considerable. Therefore, the pharmacokinetics of omeprazole were compared after intravenous (20 mg/kg) and oral (40 mg/kg) administration in control rats and in dehydrated rats. After intravenous administration, the time-averaged nonrenal clearance (Cl(nr)) values of omeprazole were comparable between the two groups of rats. This could be supported by comparable in vitro intrinsic clearance (Cl(int)) values for the disappearance of omeprazole in rat hepatic microsomes and the comparable free (unbound to plasma proteins) fractions of omeprazole in plasma in the two groups of rats. After oral administration, the AUC values of omeprazole were also comparable in the two groups of rats. The above data suggest that the dehydration state did not affect considerably the pharmacokinetics of omeprazole in rats.     

Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of torasemide in rabbits

The pharmacokinetics and pharmacodynamics of torasemide were evaluated after intravenous administration of the same total dose of torasemide at a dose of 1mg/kg to rabbits with different infusion times, 1 min (treatment I), 30 min (treatment II) and 2 h (treatment III). The loss of water and electrolytes in urine induced by torasemide was immediately replaced with infusion of an equal volume of lactated Ringer's solution. All the pharmacokinetic parameters of torasemide, such as total area under the plasma concentration-time curve from time zero to time infinity (AUC), total body clearance (CL), apparent volume of distribution at steady state (Vss), terminal half-life and mean residence time (MRT), were independent of infusion times. However, the 8 h urine output (235, 534 and 808 ml) and 8 h urinary excretion of sodium (24.2, 80.1 and 89.2 mmol) and chloride (27.1, 89.2 and 94.0 mmol) were significantly greater in treatments II and III than those in treatment I, although the total 8 h urinary excretion of unchanged torasemide (1210, 1210 and 1310 microg) were not significantly different among the three treatments. This could be due to the higher diuretic efficiencies in treatments II and III.     

Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery

Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) were obtained from healthy individuals. However, the disposition as well as the response to a given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in patients scheduled for abdominal aortic surgery. Population nonlinear mixed-effect modeling was done with Nonmem. Data were obtained from ten male patients. The TCI system (Diprifusor) was used to administer propofol. The BIS index served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. A two-compartment model was used to describe propofol PK. The typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were V(C) = 24.7 l, V(T) = 112 l, Cl = 2.64 l/min and Q = 0.989 l/min. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment with the rate constant for the distribution to the effector compartment equal to 0.240 min(-1). The BIS index was linked to the effect site concentrations through a sigmoidal E(max) model with EC(50) = 2.19 mg/l. The body weight, age, blood pressure and gender were not identified as statistically significant covariates for all PK/PD parameters. The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in patients undergoing surgery.     

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 ast _1/2 (21.4, 53.8 vs. 127 min),CL (35.8, 19.1 vs. 13.4 ml/min per kg),CL _NR (35.2, 17.8 vs. 12.6 ml/min per kg) andV _SS (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. This work was supported in part by SNU Development Foundation, 1991.     

Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects

AIMS: The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, during chronic infusions in healthy male subjects. METHODS: Tezosentan was infused at a rate of 100 mg h(-1) for 6 h (study A, six subjects) and at a rate of 5 mg h(-1) for 72 h (study B, eight subjects). Both studies had a randomized, placebo-controlled, double-blind design. Tolerability and safety were monitored by the recording of vital signs, ECG, adverse events and clinical laboratory parameters. Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin-1 concentrations. RESULTS: In both studies tezosentan was well tolerated with headache the most frequently reported adverse event (incidence of 75-100% for tezosentan and 50% for placebo). Plasma concentrations of tezosentan rapidly approached steady state (3000 and 125 ng ml(-1) in study A and B, respectively) and did not change upon prolonged infusion. A two-compartment model could describe its pharmacokinetic profile. The half-lives of the two disposition phases were approximately 0.10 and 3.2 h. Endothelin-1 concentrations increased rapidly 11- and 2-fold compared with pre-dose values in study A and B, respectively, during infusion of tezosentan and did not change during the 72 h infusion. CONCLUSIONS: On the basis of these results, dose finding studies with tezosentan in acute heart failure can be initiated in the dose range 5-100 mg h(-1).     

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

Azosemide, 5, 10, 20, and 30 mg/kg, was administered both intravenously and orally to determine the pharmacokinetics and pharmacodynamics of azosemide in rats (n=7–12). The absorption of azosemide from various segments of GI tract and the reasons for the appearance of multiple peaks in plasma concentrations of azosemide after oral administration were also investigated. After intravenous (iv) dose, the pharmacokinetic parameters of azosemide such ast _1/2, MRT, V_SS, CL, CL_R, and CL_NR were found to be dose-dependent in the dose ranges studied. The percentages of the iv dose excreted in 8-hr urine as azosemide, MI (a metabolite of azosemide), glucuronide of azosemide, and glucuronide of MI—expressed in terms of azosemide—were also dose-dependent in the dose ranges studied. The data above suggest saturable metabolism of azosemide in rats. The measurements taken after the iv administrations such as the 8 hr urine output, the total amount of sodium and chloride excreted in 8-hr urine per 100 g body weight, and diuretic, natriuretic, kaluretic, and chloruretic efficiencies were also shown to be dose-dependent. However, the total amount of potassium excreted in 8-hr urine per 100 g body weight was dose-independent. Similar dose-dependency was also observed following oral administration. Azosemide was absorbed from all regions of GI tract studied and approximately 93.5, 79.1, 86.1, and 71.5% of the doses (5, 10, 20, and 30 mg/kg, respectively) were absorbed between 1 and 24 hr after oral administration. The appearance of multiple peaks after oral administration is suspected to be due mainly to the gastric emptying pattern. The percentages of azosemide absorbed from the GI tract as unchanged azosemide for up to 24 hr after oral doses of 5, 10, 20, and 30 mg/kg were significantly different with doses (decreased with increasing doses), suggesting that the problem of azosemide precipitating in acidic gastric juices or dissolution may have at least partially influenced the absorption of azosemide after oral administration. This paper was supported in part by Non-Directed Research Fund, Korea Research Foundation, 01-F-0124, 1994. This paper is taken from a dissertation submitted by Sun H. Lee to the Graduate School, Seoul National University, in partial fulfillment of Doctor of Philosophy Degree requirements.     

Pharmacokinetics and pharmacodynamics of furosemide in protein-calorie malnutrition

The influence of dietary protein deficiency on pharmacokinetics and pharmacodynamics of furosemide was investigated after iv bolus (1 mg/100 g) and oral (2 mg/100 g) administration of furosemide to male Sprague-Dawley rats fed on a 23% (control) or a 5% (protein-calorie malnutrition: PCM) protein diet ad lib.for 4 weeks. After iv administration, the mean values of CL _R , V _{ss, and the percentages of dose excreted in 8-hr urine as furosemide were increased 81, 31, and 61%, respectively, in PCM rats when compared with those in control rats, however}, CL _NR was 54% decreased in PCM rats. The decreased CL_NR in PCM rats suggested the significantly decreased nonrenal metabolism of furosemide. The urine volume per g kidney after iv administration was not significantly different between the two groups of rats although the amount of furosemide excreted in 8-hr urine per g kidney increased significantly in PCM rats. The diuretic, natriuretic, kaluretic, and chloruretic efficiencies reduced significantly in PCM rats after iv administration. After oral administration, the extent of bioavailability increased considerably from 27.6% in control rats to 47.0% in PCM rats, probably as a result of decreased gastrointestinal and hepatic first-pass metabolism. This was supported by a tissue homogenate study; the amount of furosemide remaining per g tissue after 30-min incubation of 50 g of furosemide with the 9000 × gsupernatant fraction of stomach (42.4 vs. 47.9 g) and liver (41.4 vs. 45.9 g) homogenates increased significantly in PCM rats. No significant differences in CL_R and t_1/2 were found between the control and the PCM rats after oral administration. The 24-hr urine volume and the amount of sodium excreted in 24-hr urine per g kidney increased significantly in PCM rats, and this might be due to a significantly increased amount of furosemide reaching the kidney excreted in urine per g kidney.This work was supported in part by a research grant from the Korea Science and Engineering Foundation, 1990–1992.     

Pharmacokinetics and pharmacodynamics of intravenous and inhaled fluticasone furoate in healthy Caucasian and East Asian subjects

AIM

The aim of the study was to evaluate the pharmacokinetics (PK) of inhaled and intravenous (i.v.) fluticasone furoate (FF) in healthy Caucasian, Chinese, Japanese and Korean subjects.

METHOD

This was an open label, randomized, two way crossover study in healthy Caucasian, Chinese, Japanese and Korean subjects (n = 20 per group). Inhaled FF (200 μg for 7 days, then 800 μg for 7 days from a dry powder inhaler [DPI]) was administered in one treatment period and i.v.FF (250 μg infusion) in the other. FF PK and serum cortisol (inhaled 200 μg only) were compared between the ethnic groups using analysis of variance. P450 CYP3A4 activity and safety were also assessed.

RESULTS

Ethnic differences in i.v. FF PK were accounted for by body weight differences. CYP3A4 activity was similar across the groups. Higher FF systemic exposure was seen following inhaled dosing in Chinese, Japanese and Korean subjects compared with Caucasian subjects. Absolute bioavailability was greater (36%–55%) in all East Asian groups than for Caucasian subjects following inhaled FF 800 μg. Deconvolution analysis suggested inhaled FF resided in the lung of East Asian subjects longer than for Caucasians (time for 90% to be absorbed [t90]: 29.1–30.8 h vs. 21.4 h). In vitro simulation method predicted comparable delivered lung dose across ethnic groups. Serum cortisol weighted mean was similar between Caucasians and Chinese or Koreans, while in Japanese was on average 22% lower than in Caucasians. All FF treatments were safe and well tolerated.

CONCLUSION

Modestly higher (<50%) FF systemic exposure seen in East Asian subjects following inhaled dosing was not associated with a clinically significant effect on serum cortisol, suggesting that a clinical dose adjustment in East Asian subjects is not required.     

Pharmacokinetics of phenytoin and its metabolite, 4'-HPPH, after intravenous and oral administration of phenytoin to diabetic rats induced by alloxan or streptozotocin

It has been reported that diabetic patients have an increased risk of developing epileptic convulsions compared with the non-diabetic population, and phenytoin has widely been used for neuralgia in diabetic neuropathy. It has also been reported that in both diabetic rats induced by alloxan (DMIA rats) and by streptozotocin (DMIS rats), the protein expression and mRNA level of 2C11 decreased, but in DMIS rats, the protein expression of CYP2C6 increased. Thus, the pharmacokinetics of phenytoin and 4'-HPPH were investigated after intravenous or oral administration of phenytoin at a dose of 25 mg/kg to DMIA and DMIS rats. After intravenous or oral administration of phenytoin, the AUC (or AUC(0-12 h)) values of both phenytoin and 4'-HPPH were comparable (not significantly different) between each diabetic and the respective control rats. Although the exact reason is not clear, this could have been due to opposite protein expression (and/or mRNA levels) of CYP2C6 and 2C11 in diabetic rats.     

Effects of naringin on the pharmacokinetics of intravenous paclitaxel in rats

It was reported that paclitaxel is an inhibitor of hepatic P-glycoprotein (P-gp) and hepatic microsomal cytochrome P450 (CYP) 3A1/2, and that naringin is an inhibitor of biliary P-gp and CYP3A1/2 in rats. The purpose of this study was to report the effects of oral naringin on the pharmacokinetics of intravenous paclitaxel in rats. Oral naringin (3.3 and 10 mg/kg) was pretreated 30 min before intravenous (3 mg/kg) administration of paclitaxel. After intravenous administration of paclitaxel, the AUC was significantly greater (40.8% and 49.1% for naringin doses of 3.3 and 10 mg/kg, respectively), and Cl was significantly slower (29.0% and 33.0% decrease, respectively) than controls. The significantly greater AUC could be due mainly to an inhibition of metabolism of paclitaxel via CYP3A1/2 by oral naringin. The inhibition of hepatic P-gp by oral naringin could also contribute to the significantly greater AUC of intravenous paclitaxel by oral naringin.