So H. Kim

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 CLR, Vss, 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, CLNRwas 54% decreased in PCM rats. The decreased CLNRin 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 μg of furosemide with the 9000 × gsupernatant fraction of stomach (42.4 vs. 47.9 μg) and liver (41.4 vs. 45.9 μg) homogenates increased significantly in PCM rats. No significant differences in CLRand t1/2were 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.

Liver and Gastrointestinal First-pass Effects of Azosemide in Rats

Since considerable first‐pass effects of azosemide have been reported after oral administration of the drug to rats and man, first‐pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats.

Interspecies pharmacokinetic scaling of a new carbapenem, DA-1131, in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics

The total body clearance (Cl), renal clearance (Clr), and apparent volume of distribution at steady state (Vss) of DA‐1131, a new carbapenem, after intravenous (iv) administration of the drug, 50 mg kg−1, to mice, rats, rabbits, and dogs were analysed as a function of species body weight (W) using the allometric equation for interspecies scaling, and were used to predict these parameters in humans. Significant linear relationships were obtained between log[Cl (L h−1)] and log[W (kg)] (r = 0.995; p = 0.00503), log[Clr (L h−1)] and log[W (kg)] (r = 0.998; p = 0.0429), and log[Vss (L)] and log[W (kg)] (r = 0.987; p = 0.0126). The corresponding allometric equations were Cl = 0.706W0.811, Clr = 0.318W0.888, and Vss = 0.194W0.981. These allometric equations were extrapolated to predict the Cl and Vss for DA‐1131 in humans based on 70 kg body weight. The Cl and Vss for humans predicted from the four animal data well fitted to regression lines of animal data. Interspecies scale‐up of plasma concentration–time data for the four species using a complex Dedrick plot resulted in similar profiles. In addition, the concentration in plasma–time profile predicted using the four animal data well fitted to a complex Dedrick plot of animal data. Our results indicate that the DA‐1131 data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters in humans. These parameters can serve as guidelines for better planning of clinical studies.

Pharmacokinetics of Liquiritigenin in Mice, Rats, Rabbits, and Dogs, and Animal Scale-Up

Pharmacokinetics of liquiritigenin (LQ) and its two glucuronide metabolites, M1 and M2, in mice, rats, rabbits, and dogs and animal scale-up of the pharmacokinetic parameters of LQ were evaluated. After intravenous administration of LQ, the AUC (AUC(0-t)) values of LQ, M1, and M2 were proportional to LQ doses in all animals studied. Animal scale-up of some pharmacokinetic parameters of LQ was performed based on the parameters after its intravenous administration (20 mg/kg; in the linear pharmacokinetic range) to the four species. Linear relationships were obtained (r > 0.968) between log CL (or CL/f(u)) (L/h) and log species body weight (W) (kg) [CL (or CL/f(u)) = 3.29 (34.0) W(0.723 (0.789))] and log V(ss) (or V(ss)/f(u)) (L) and log W (kg) [V(ss) (or V(ss)/f(u)) = 0.340 (3.52) W(0.882 (0.948))]. Interspecies scale-up of plasma concentration-time data of LQ using apolysichron (complex Dedrick plots) resulted in similar profiles, and plasma concentration-time profile of humans were predicted using the well-fitted four animal data. Our results indicate that the LQ data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters of LQ in humans. These parameters can serve as guidelines for better planning of clinical studies.

Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous ipriflavone in rats.

In order to find out what types of the hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of ipriflavone, ipriflavone at a dose of 20 mg kg−1 (or 15 mg kg−1) was infused in male Sprague—Dawley rats. In rats pretreated with SKF 525‐A (a non‐specific CYP isozyme inhibitor in rats), the total body clearance (CL) of ipriflavone was significantly slower (29.9% decrease) than that in control rats. This indicates that ipriflavone is metabolized via CYP isozymes in rats, hence various enzyme inducers and inhibitors were used in in‐vitro or in‐vivo studies in rats. In rats pretreated with 3‐methylcholanthrene and phenobarbital (main inducers of CYP1A1/2 and 2B1/2 in rats, respectively), the CL values were significantly higher (153 and 67.2% increases, respectively). In rats pretreated with sulfaphenazole (a main inhibitor of CYP2C11 in rats), the CL was significantly slower (22.5% decrease) than that in control rats. On addition of furafylline (a main inhibitor of CYP1A2 in rats), the in‐vitro intrinsic clearance for the disappearance of ipriflavone was significantly slower (50.8% decrease) than that without furafylline. However, the CL values were not significantly different in rats pretreated with orphenadrine and isoniazid (a main inducer of CYP2E1 in rats), and quinine and troleandomycin (main inhibitors of CYP2D1 and 3A23/2 in rats, respectively) compared to controls. These data suggest that ipriflavone could be metabolized mainly via CYP1A1/2, 2B1/2 and 2C11 in rats.

Pharmacokinetics of a new carbapenem, DA-1131, after intravenous administration to rats with alloxan-induced diabetes mellitus

Because physiological changes occurring in diabetes patients could alter the pharmacokinetics of drugs used to treat the disease, the pharmacokinetics and tissue distribution of DA‐1131, a new carbapenem antibiotic, were investigated after 1‐min intravenous (iv) administration of the drug, 50 mg kg−1, to control and alloxan‐induced diabetes mellitus (AIDM) rats. The impaired kidney function was observed by pretreatment with alloxan based on physiological parameters of plasma, creatinine clearance, and the kidney microscopy. After 1‐min iv infusion of DA‐1131, the plasma concentrations of DA‐1131 and the total area under the plasma concentration–time curve of DA‐1131 from time zero to time infinity (AUC) increased significantly in the AIDM rats (7350 versus 4400 μg min mL−1) when compared with those in control rats. This was due to significantly slower total body clearance (Cl) of DA‐1131 (6.80 versus 11.4 mL min−1 kg−1) in AIDM rats than that in control rats. The significantly slower Cl of DA‐1131 in AIDM rats was due to significantly slower renal (2.62 versus 4.95 mL min−1 kg−1, because of the considerably decreased glomerular filtration rate of DA‐1131) and nonrenal (3.99 versus 6.34 mL min−1 kg−1, possibly because of the considerably slower metabolism in rat liver and kidney) clearance in AIDM rats. The amount of DA‐1131 recovered from each rat tissue studied was significantly higher in AIDM rats than that in control rats, however, the tissue to plasma ratios were not significantly different between the two groups of rats.

Effect of CYP3A1 (23) Induction on Clarithromycin Pharmacokinetics in Rats with Diabetes Mellitus

ABSTRACT After intravenous and oral administration of clarithromycin at a dose of 20 mg/kg of body weight to rats with diabetes mellitus induced by alloxan (DMIA) and diabetes mellitus induced by streptozotocin (DMIS), the area under the curve values were significantly smaller than those of respective control rats. The in vitro intrinsic clearance values for the disappearance of clarithromycin were significantly faster in both rats with DMIA and rats with DMIS than in control rats. The above data suggested that metabolism of clarithromycin increased in both types of diabetic rat due to an increase in the expression and mRNA level of CYP3A1(23) in the rats.

Pharmacokinetics and tissue distribution of a new carbapenem, DA-1131, after intravenous administration to mice, rats, rabbits and dogs

The pharmacokinetic parameters including tissue distribution and/or biliary excretion of DA‐1131, a new carbapenem, were evaluated after intravenous (iv) administration to mice, rats, rabbits, and dogs. After iv administration to mice (20, 50, 100, and 200 mg kg−1), rats (50, 100, 200, and 500 mg kg−1), rabbits (20, 50, 100, and 200 mg kg−1), and dogs (10, 20, 50, 100, and 200 mg kg−1), the pharmacokinetic parameters of DA‐1131 seemed to be independent of DA‐1131 doses studied in all four animal species. However, the renal clearance and percentage of iv dose of DA‐1131 excreted in 24 h urine as unchanged drug decreased significantly in rabbits (from 200 mg kg−1) and dogs (from 100 mg kg−1) due to reduced kidney function induced by DA‐1131. The creatinine clearance decreased significantly in rabbits at 200 mg kg−1 compared with that in the control rabbits (0.466 versus 4.31 mL min−1 kg−1). Renal active secretion of DA‐1131 was observed in rabbits and was less considerable in rats, but renal active reabsorption of DA‐1131 was observed in dogs. Although DA‐1131 was widely distributed in all tissues studied in mice (20–200 mg kg−1), rats (200 mg kg−1), rabbits (50 mg kg−1), and dogs (50 mg kg−1), affinity of DA‐1131 for tissues was low: the tissue‐to‐plasma concentration ratios were greater than unity only in the kidney and/or liver. The low affinity of DA‐1131 for tissues was also supported by relatively low values of the apparent volume of distribution at steady state in rats (147–187 mL kg−1), rabbits (91.7–148 mL kg−1), and dogs (243–298 mL kg−1). The contribution of biliary excretion of unchanged DA‐1131 to nonrenal clearance of DA‐1131 seemed to be minor in rats (200 mg kg−1) and dogs (50 mg kg−1); the percentages of iv dose excreted in 8 h bile as unchanged DA‐1131 were 1.76 and 2.71% after iv administration of the drug to rats and dogs, respectively.

Pharmacokinetics of ipriflavone and its two metabolites, M1 and M5, after the intravenous and oral administration of ipriflavone to rat model of diabetes mellitus induced by streptozotocin.

Ipriflavone was reported to be primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2 and 2C11 in male Sprague-Dawley rats. The protein expression and/or mRNA levels of hepatic CYP1A subfamily and 2C11 was reported to be increased and decreased, respectively, in diabetic rats induced by streptozotocin (DMIS rats). Thus, the pharmacokinetic parameters of ipriflavone and its two metabolites, M1 and M5, were compared after the i.v. (20mg/kg) and p.o. (200mg/kg) administration of ipriflavone to control and DMIS rats. After both i.v. and p.o. administration of ipriflavone to DMIS rats, the AUCs of ipriflavone were significantly smaller (by 31.7% and 34.2% for i.v. and p.o. administration, respectively) than controls. The faster Cl(nr) (smaller AUC) of i.v. ipriflavone could have been due to the faster hepatic Cl(int) (because of an increase in the protein expression and/or mRNA level of hepatic CYP1A subfamily) and the faster hepatic blood flow rate than controls. The smaller AUC of p.o. ipriflavone in DMIS rats could have mainly been due to the faster intestinal Cl(int) (because of an increase in the intestinal CYP1A subfamily) than controls.

Effects of enzyme inducers or inhibitors on the pharmacokinetics of intravenous parathion in rats.

In order to find what form of hepatic cytochrome P450 (CYP) is involved in the metabolism of parathion to form paraoxon, rats were pretreated with the enzyme inhibitors, such as SKF 525‐A and ketoconazole or enzyme inducers, such as dexamethasone, isoniazid, phenobarbital, and 3‐methylcholanthrene. Parathion, 3 mg/kg, was infused in 1 min via the jugular vein. In rats pretreated with SKF 525‐A or ketoconazole, nonspecific CYP inhibitors, the area under the plasma concentration–time curve from time zero to time infinity (AUC) and total body clearance (Cl) of parathion were significantly greater and slower, respectively, than those in respective control rats, suggesting that parathion was metabolized by CYPs. In rats pretreated with dexamethasone (CYP3A23 inducer), the AUC was significantly smaller (41.5 compared with 52.5 µg min/mL), Cl was significantly faster (72.2 compared with 57.1 mL/min/kg), and the amounts and/or tissue‐to‐plasma ratios of parathion was significantly (or tended to be) smaller than those in control rats. However, the pharmacokinetic parameters of parathion were not significantly different after pretreatment with other enzyme inducers compared with respective control rats. The above data suggested that parathion was metabolized to paraoxon by dexamethasone‐inducible CYP3A23, the induction of which was confirmed by Western blot analysis. This was supported by in vitro intrinsic clearance (Clint) of parathion to form paraoxon in hepatic microsomal fraction; the Clint in rats pretreated with dexamethasone was significantly faster (0.0900 compared with 0.0290 mL/min/mg protein) than that in control rats. Copyright