Effects of bile salts on the lovastatin pharmacokinetics following oral administration to rats.

This study aimed to examine the effects of bile salts on pharmacokinetics of lovastatin, which has low bioavailability. Lovastatin solid dispersions were prepared using sodium deoxycholate (NaDC) and sodium glycholate (NaGC) at ratios of 1:19, 1:49, and 1:69. The formulated solid dispersions and control (commercial tablet) were administered to rats and plasma concentrations were determined by a validated LC-MS/MS method. Statistically significant differences were found in C(max), AUC0₋10, and AUC0₋∞ values among lovastatin formulations (p < 0.05). NaDC-containing formulations revealed higher bioavailabilities than NaGC-containing solid dispersions at ratios of 1:19 and 1:49. Especially, NaDC-containing formulation at a ratio of 1:19 (NaDC19) showed the highest bioavailability. The AUC (both AUC0₋10 and AUC0₋∞) of NaDC19 was statistically higher than control and NaDC69 (p < 0.05). The AUC values decreased as bile salt concentrations increased. Overall, formulations containing bile salts showed higher AUC values than control, even though all formulations did not show significantly higher AUC. In conclusion, the addition of bile salts to lovastatin could enhance drug bioavailabilities. However, too high concentrations of bile salts could decrease bioavailabilities of lovastatin.

Pharmacokinetics of oltipraz in mutant Nagase analbuminemic rats.

Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (50 mg/kg) administration to control male Sprague-Dawely rats and mutant Nagase analbuminemic rats (NARs). In NARs, the expression and mRNA level of CYP1A2 increased, and oltipraz was mainly metabolized via CYP1A1/2, 2B1/2, 2C11, 201, and 3A1/2 in male rats. Hence, it may be expected that the CL of oltipraz would be significantly faster in NARs. This was proven by the following results. After intravenous administration, the CL of oltipraz was significantly faster in NARs (125% increase) than controls due to significantly greater free fractions (unbound to plasma proteins) of oltipraz (197% increase) and significantly faster CL(int) for the disappearance of oltipraz (11.4% increase) in NARs, since oltipraz is an intermediate hepatic extraction ratio drug in rats. The V(ss) was significantly larger in NARs (109% increase) and this could be due to significant increase in free fractions of oltipraz in NARs. After oral administration, the AUC of oltipraz was also significantly smaller in NARs (61.9% decrease). This could also be due to significant increase in free fractions of oltipraz and significantly faster CL(int) in NARs. However, this was not due to decrease in absorption in NARs.

Pharmacokinetics and therapeutic effects of oltipraz after consecutive or intermittent oral administration in rats with liver cirrhosis induced by dimethylnitrosamine.

Pharmacokinetics and therapeutic effects of oltipraz were evaluated after consecutive (once per day at 30 mg/kg/day for 7 and 14 days) or intermittent (once per week at 100 mg/kg/week for 1-3 weeks) oral administration to rats with liver cirrhosis induced by dimethylnitrosamine. The AUC of oltipraz was significantly greater in cirrhotic rats than controls (890 compared with 270 microg . min/mL) due to impaired liver function in cirrhotic rats. However, the AUC values after consecutive 7 (421 compared with 753 microg . min/mL) and 14 (309 compared with 821 microg . min/mL) days oral administration of oltipraz in cirrhotic rats were significantly smaller than those in respective vehicle-treated cirrhotic rats. Moreover, the AUC values after intermittent 2 and 3 weeks in cirrhotic rats were also significantly smaller than that in 1 week vehicle-treated cirrhotic rats (2370 and 1690 compared with 4760 microg . min/mL). This could be due to induction of CYP isozymes and considerably greater numbers of normal liver cells in cirrhotic rats by oral administration of oltipraz. Improved liver function by oltipraz in cirrhotic rats was proved by liver microscopy; livers are free of significant fibrosis, although evidence of bridging necrosis is still present in many rats.

Pharmacokinetics of oltipraz in rat models of diabetes mellitus induced by alloxan or streptozotocin.

Pharmacokinetic parameters of oltipraz were compared after intravenous (10 mg/kg) and oral (30 mg/kg) administration in rat model of diabetes mellitus induced by alloxan (rat model of DMIA) or streptozotocin (rat model of DMIS) and their respective control male Sprague-Dawley rats. In rat models of DMIA and DMIS, the expressions and mRNA levels of CYP1A2, 2B1/2, and 3A1(23) increased, and oltipraz was metabolized mainly via CYP1A1/2, 2B1/2, 2C11, 2D1, and 3A1/2 in male Sprague-Dawley rats. Hence, it would be expected that the AUC and CL values of oltipraz would be significantly smaller and faster, respectively, in rat models of diabetes. This was proven by the following results. After intravenous administration, the AUC values were significantly smaller in rat models of DMIA (40.1% decrease) and DMIS (26.0% decrease) than those in respective control rats, and this could be due to significantly faster CL values in rat models of DMIA (40.1% increase) and DMIS (26.0% increase). The faster CL could be due to increase in hepatic blood flow rate and significantly faster CL(int) in rat models of diabetes, since oltipraz is an intermediate hepatic extraction ratio drug in male Sprague-Dawley rats. After oral administration, the AUC values of oltipraz were also significantly smaller in rat models of DMIA (54.0% decrease) and DMIS (63.2% decrease). This could be due to increase in hepatic blood flow rate, significantly faster CL(int), and changes in the intestinal first-pass effect in rat models of diabetes. However, this was not due to decrease in absorption in rat models of diabetes.

Effects of cysteine on the pharmacokinetics of oltipraz in rats with protein-calorie malnutrition.

Effects of cysteine on the pharmacokinetics of oltipraz were investigated after iv (10 mg/kg) and oral (30 mg/kg) administration to male control, protein-calorie malnutrition (PCM), and PCM with oral cysteine supplementation (PCMC) rats. It was reported that oltipraz was mainly metabolized via hepatic CYP1A1/2, 2B1/2, 2C11, 3A1/2, and 2D1 in male rats. The expression and mRNA levels of CYP1A2, 2C11, and 3A1/2 were also reported to decrease in male PCM rats compared with controls. Interestingly, the decreased CYP isozymes in PCM rats returned fully or partially to controls by oral cysteine supplementation (PCMC rats). Hence, it would be expected that in PCM rats, some pharmacokinetic parameters of oltipraz are fully or partially returned to controls by cysteine. This was proven by the following parameters in PCMC rats: the AUC (328, 782, and 416 mug min/mL for control, PCM, and PCMC rats, respectively, after iv administration, and 223, 456, and 242 mug min/mL after oral administration), terminal half-life (130, 212, and 143 min), mean residence time (MRT) (149, 299, and 189 min), and in vitro CL(int) (0.181, 0.107, and 0.153 mL/min/mg protein) were fully returned to controls, and CL and CL(NR) values were partially returned to controls.

Effect of enzyme inducers and inhibitors on the pharmacokinetics of oltipraz in rats.

A series of in-vitro and in-vivo experiments, using various inducers and inhibitors of hepatic microsomal cytochrome P450 (CYP) isozymes, was conducted to study oltipraz pharmacokinetics in rats. In in-vivo studies, oltipraz at a dose of 10 mg kg(-) was administered intravenously to rats. In rats pretreated with SKF 525-A (a nonspecific CYP isozyme inhibitor in rats; n-9), the time-averaged total body clearance (CL) of oltipraz was significantly slower (56.6% decrease) than that in untreated rats (n=9). This indicated that oltipraz is metabolized via CYP isozymes in rats. Hence, various enzyme inducers or inhibitors were used in in-vitro and in-vivo studies in rats. In rats pretreated with 3-methylcholanthrene (n=9 and 8 for untreated and treated groups, respectively), phenobarbital (n=7 and 10 for untreated and treated groups, respectively) or dexamethasone (n=7 and 12 for untreated and treated groups, respectively) (main inducers of CYP1A1/2, 2B1/2 and 3A1/2 in rats, respectively), the CL values were significantly faster (38.4, 94.4 and 33.6% increase, respectively). In rats pretreated with sulfaphenazole (n=8 and 9 for untreated and treated groups, respectively), quinine (n=7 and 9 for untreated and treated groups, respectively) or troleandomycin (n=8 and 9 for untreated and treated groups, respectively) (main inhibitors of CYP2C11, 2D1 and 3A1/2 in rats, respectively), the CL values were significantly slower (31.0, 27.6 and 36.3% decrease, respectively). The in-vivo results with various enzyme inhibitors correlated well with the in-vitro intrinsic clearance for disappearance of oltipraz (CL(int)) (n=5, each). The above data suggested that oltipraz could be metabolized in male rats mainly via CYP1A1/2, 2B1/2, 2C11, 3A1/2 and 2D1.

Interspecies pharmacokinetic scaling of oltipraz in mice, rats, rabbits and dogs, and prediction of human pharmacokinetics.

Dose-independent pharmacokinetics of oltipraz after intravenous and/or oral administration at various doses to mice, rats, rabbits and dogs were evaluated. After both intravenous and/or oral administration of oltipraz to mice (5, 10 and 20 mg/kg for intravenous and 15, 30 and 50 mg/kg for oral administration), rats (5, 10 and 20 mg/kg for intravenous and 25, 50 and 100 mg/kg for oral administration), rabbits (5, 10 and 30 mg/kg for intravenous administration) and dogs (5 and 10 mg/kg for intravenous and 50 and 100 mg/kg for oral administration), the total area under the plasma concentration-time curve from time zero to time infinity (AUC) values of oltipraz were dose-proportional in all animals studied. Animal scale-up of some pharmacokinetics parameters of oltipraz was also performed based on the parameters after intravenous administration at a dose of 10 mg/kg to mice, rats, rabbits and dogs. Linear relationships were obtained between log time-averaged total body clearance (Cl) x maximum life-span potential (MLP) (1 year/h) and log species body weight (W) (kg) (r=0.999; p=0.0015), log Cl (l/h) and log W (kg) (r=0.979; p=0.0209), and log apparent volume of distribution at steady state (V(ss)) (l) and log W (kg) (r=0.999; p=0.0009). The corresponding allometric equations were ClxMLP=49.8 W(0.861), Cl=5.20 W(0.523) and V(ss)=4.46 W(0.764). Interspecies scale-up of plasma concentration-time data for the four species using pharmacokinetic time of dienetichron resulted in similar profiles. In addition, concentrations of oltipraz in a plasma concentration-time profile for humans predicted using the four animal data fitted to the dienetichron time transformation of animal data.

Effect of high-density lipoprotein associated cyclosporine on hepatic metabolism and renal function.

Cyclosporine (CSA), in both humans and animals, is associated with plasma lipoproteins. It has been demonstrated that CSA-lipoprotein association is partly responsible for the distribution and toxicity related to CSA use. Altered plasma lipoprotein profiles are often seen in transplantation recipients undergoing CSA treatment. In the present study, daily 0.1 mg/kg intravenous injections of either high-density lipoprotein-associated CSA (HDL-CSA), plasma-associated CSA (Plasma-CSA), or CSA in Cremophor (CSA) were administered to adult male rats for 14 days. Vehicle controls included daily administrations of 0.5 ml/kg of Cremophor or saline. Serum creatinine levels, a marker of renal function, increased in rats administered Plasma-CSA as compared with control rats treated with CSA. CYP3A and CYP2C11 protein expression was suppressed by 27% and 39%, respectively, in the HDL-CSA treatment group and by 38% and 40% in the Plasma-CSA treated group as compared with CSA controls. In addition, 6beta-hydroxytestosterone, a marker of CYP3A activity, was reduced by 33% and 34% in the HDL-CSA and the Plasma-CSA treatment groups, respectively, as compared with the CSA control group. CYP2C11 activity was measured by the in vitro formation of 2alpha-hydroxytestosterone. Activity levels in rats treated with HDL-CSA and Plasma-CSA were slightly induced as compared to CSA controls, however these differences were not found to be statistically significant. In summary, Plasma-CSA treatment resulted in renal dysfunction and suppressed CYP3A and CPY2C11 protein expression. These results demonstratethat intravenous lipoprotein-associated CSA alters the metabolism of CSA in the rat differently than CSA alone.

The effect of lipoprotein-associated cyclosporine on drug metabolism and toxicity in rats.

PURPOSE: The objective of the study was to examine the effect of lipoprotein-associated cyclosporine on hepatic metabolism, hepatic lipoprotein receptors, and renal toxicity in comparison to the current commercially available cyclosporine (CSA) product. METHODS: Rats within the same group were given one of the following treatments: 10 mg/kg of CSA, plasma-CSA, very low-density lipoprotein (VLDL)-CSA, low-density lipoprotein (LDL)-CSA, LDL, high-density lipoprotein (HDL)-CSA, 1 mL/kg of vehicle, or saline intravenously for 14 days. Urine and blood samples were evaluated for renal function. Hepatic microsomes were prepared for immunoblotting and in vitro catalytic assays of CYP activity. Reverse transcription polymerase chain reaction (RT-PCR) was used to examine genetic regulation. RESULTS: (1) There were no statistical differences in cholesterol levels in lipoprotein-associated CSA groups as compared with vehicle controls. (2) A significant decrease in creatinine clearance was seen in the plasma-CSA treated group (56%; P < 0.05). (3) No suppressions of CYP3A protein, activity or mRNA were found in the VLDL-CSA treated group. (4) CYP3A mRNA was suppressed to a greater degree in the LDL- and HDL-CSA treated groups as compared with the suppression caused by CSA alone. (5) A significant suppression of hepatic low-density lipoprotein receptor (LDL-R) mRNA levels was found in the LDL-CSA (50%; P = 0.0333) and plasma-CSA (40%; P = 0.1138), which was not attributed to LDL alone. (6) Significant suppression of scavenger-receptors class B type I (SR-BI) mRNA levels was found in the plasma-CSA group, although no significant differences in SRBI protein levels were seen between groups. CONCLUSIONS: Specific lipoprotein-CSA complexes appear to alter metabolic responses differently in comparison to CSA alone, indicating that the metabolism of CSA is dependent on the in vivo disposition of lipoprotein-CSA. Furthermore, LDL-R is one regulatory factor responsible for altering CSA metabolism as a result of an increase in uptake of CSA into hepatocytes.