Effects of Escherichia coli lipopolysaccharide on the metformin pharmacokinetics in rats

1. The time-dependent (2-h, 24-h, and 96-h) effects of Escherichia coli lipopolysaccharide (ECLPS) on the intravenous (100?mg kg^?1) and oral (100?mg kg^?1) metformin pharmacokinetics were evaluated in rats.

2. After the intravenous administration of metformin to 24-h and 96-h ECLPS rats, the total area under the plasma concentration–time curve from time zero to time infinity (AUCs) and time-averaged non-renal clearances (CL_NRs) of metformin were significantly greater and slower, respectively, than the controls. However, after the oral administration of metformin, the AUCs of metformin were comparable among four groups of rats.

3. The greater (slower) intravenous AUCs (CL_NRs) of metformin in 24-h and 96-h ECLPS rats were due to the slower hepatic intrinsic clearance (CL_int) because of a decrease in the protein expression of hepatic cytochrome P450 (CYP) 2C11 and/or CYP3A subfamily than controls. The comparable oral AUCs among four groups of rats were mainly due to the comparable gastrointestinal metabolism (CL_int).

     

Faster clearance of mirodenafil in rats with acute renal failure induced by uranyl nitrate: contribution of increased protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2

Objectives It has been reported that mirodenafil is primarily metabolized via hepatic cytochrome P450 (CYP) 1A1/2, 2B1/2, 2D1 and 3A1/2 in rats. It has also been reported that the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 increases and that of hepatic CYP2D1 decreases in rats with acute renal failure induced by uranyl nitrate (U‐ARF rats). Thus, the pharmacokinetics of mirodenafil were studied in control and U‐ARF rats. Methods The pharmacokinetic parameters of mirodenafil and SK3541 (a metabolite of mirodenafil) were compared after the intravenous and oral administration of mirodenafil at a dose of 20 mg/kg to U‐ARF and control rats. Key findings After interavenous administration of mirodenafil to U‐ARF rats, the total area under the concentration–time curve (AUC) of mirodenafil was significantly smaller (36.5% decrease) than controls, possibly due to the significantly faster non‐renal clearance (66.1% increase; because of increase in the protein expression of hepatic CYP3A1) than controls. After the oral administration of mirodenafil to U‐ARF rats, the AUC of mirodenafil was also significantly smaller (47.8% decrease) due to the increase in the protein expression of hepatic CYP3A1 and intestinal CYP1A1 and 3A1/2 compared with controls. Conclusions After both intravenous and oral administration of mirodenafil to U‐ARF rats, the AUC_SK3541/AUC_mirodenafil ratios were comparable with that in controls and this could be due to further metabolism of SK3541 in rats.     

Use of uptake intrinsic clearance from attached rat hepatocytes to predict hepatic clearance for poorly permeable compounds

1. We previously reported that the accuracy of clearance (CL) prediction could be differentiated by permeability. CL was drastically under-predicted by in vitro metabolic intrinsic clearance (CL_int) for compounds with low permeability (<5?×?10^?6 cm/s).

2. We determined apparent uptake CL_int by measuring initial disappearance from medium using attached rat hepatocytes and metabolic CL_int by measuring parent depletion in suspended rat hepatocytes (cells and medium).

3. Uptake and metabolic CL_int were comparable for highly permeable metabolic marker compounds. In contrast, uptake CL_int was 3- to 40-fold higher than metabolic CL_int for rosuvastatin, bosentan, and 15 proprietary compounds, which had low permeability, suggesting that uptake could be a rate-determining step in hepatic elimination for these poorly permeable compounds.

4. The prediction of hepatic CL was improved significantly when using uptake CL_int for the compounds with low permeability. The average fold error was 2.2 and 6, as opposed to >11 and >47 by metabolic CL_int, with and without applying a scaling factor of 4, respectively.

5. Uptake CL_int from attached hepatocytes can be used as an alternative approach to predict hepatic clearance and to understand the significance of hepatic uptake in elimination in an early drug discovery setting.

     

Pharmacokinetics of liquiritigenin and its two glucuronides,M1 and M2, in rats with acute hepatitis induced by d-galactosamine/lipopolysaccharide or CCl4

1. Cytoprotective effects of liquiritigenin (LQ) against liver injuries have been reported, but its pharmacokinetics has not been studied in acute hepatitis. Thus, pharmacokinetics of LQ and its two conjugated glucuronide metabolites: 4′-O-glucuronide (M1) and 7-O-glucuronide (M2), in rats with acute hepatitis induced by d-galactosamine/lipopolysaccharide (GalN/LPS) rats or carbon tetrachloride-treated (CCl₄-treated) rats were evaluated.

2. LQ was administered intravenously (20?mg kg^?1) and orally (50?mg kg^?1) to control GalN/LPS and CCl₄-treated rats. Expression of uridine 5′-diphospho-glucuronosyltransferases 1A (UGT1A) and in vitro metabolism of LQ in hepatic and intestinal microsomes were also measured.

3. After intravenous administration of LQ, area under the plasma concentration-time curve (AUC) of LQ in GalN/LPS rats was significantly smaller than that in controls due to faster non-renal clearance, as a result of its greater free fraction in plasma and faster hepatic blood flow rate than the controls. In CCl₄-treated rats, the AUC_{M1, 0?8 h}/AUC_LQ and AUC_{M2, 0?8 h}/AUC_LQ ratios were significantly greater than the controls due to decrease in biliary excretion of M1 and M2. However, no significant pharmacokinetic changes were observed in both acute hepatitis rats after oral administration due to comparable intestinal metabolism of LQ.

4. Modification of oral dosage regimen of LQ may not be necessary in patients with acute hepatitis; but human studies are required.

     

Cysteine effects on the pharmacokinetics of etoposide in protein–calorie malnutrition rats: increased gastrointestinal absorption by cysteine

1. Protein–calorie malnutrition (PCM) occurs frequently in advanced cancer patients and has a profound impact on the toxicity of many drugs. Thus, the pharmacokinetics of etoposide were evaluated in control, control with cysteine (CC), PCM, and PCM with cysteine (PCMC) rats.

2. Etoposide was administered intravenously (2?mg/kg) or orally (10?mg/kg). Changes in hepatic and intestinal cytochrome P450s (CYPs) and effects of cysteine on intestinal P-glycoprotein (P-gp)-mediated efflux were also measured.

3. In PCM rats, the CL_NR (AUC_0–∞) of intravenous etoposide was significantly slower (greater) than that in controls, because of the significant decrease in the hepatic CYP3A subfamily and P-gp. In PCMC rats, the slowed CL_NR of etoposide in PCM rats was restored to the control level by cysteine treatment. PCMC rats showed a significantly greater AUC_{0–6 h} of oral etoposide than PCM rats, primarily because of the increased gastrointestinal absorption of etoposide as a result of the inhibition of intestinal P-gp by cysteine.

4. The gastrointestinal absorption of an oral anticancer drug, which is a substrate of P-gp, may be improved by co-administration of cysteine in advanced cancer patients if the present rat data can be extrapolated to patients.

     

Sex differences in pharmacokinetics of cilostazol in rats

1. The pharmacokinetics of cilostazol was investigated after oral and intravenous administration in both male and female rats. After oral administration, area under serum concentration–time curve (AUC) was about 35-fold higher in female rats than in male rats, and absolute bioavailability was about 5.8-fold higher in female rats than in male rats.

2. Total body clearance (CL_total) for female rats was around one-sixth of that for male rats. In vivo hepatic clearance (CL_h) calculated based on isolated liver perfusion studies was even higher than or around 90% of the in vivo CL_total of cilostazol for female and male rats, respectively, indicating that cilostazol is mainly eliminated by the liver in both male and female rats.

3. In vitro metabolism studies utilizing hepatic microsomes and recombinant cytochrome (CYP) isoforms clearly indicated that major metabolites of cilostazol were generated extensively with hepatic microsomes of male rats and that male-predominant CYP3A2 and male-specific CYP2C11 were mainly responsible for the hepatic metabolism of cilostazol. Therefore, the great sex differences in the pharmacokinetics of cilostazol were mainly attributed to the large difference in hepatic metabolism.

4. Our experimental results also suggested that the substantial metabolism of cilostazol in the small intestine and its possible saturation would be responsible for dose-dependent bioavailability in both male and female rats.

     

Telithromycin Pharmacokinetics in Rat Model of Diabetes Mellitus Induced by Alloxan or Streptozotocin

Purpose  It has been reported that telithromycin is primarily metabolized via hepatic CYP3A1/2 in rats, the expression and/or mRNA level of hepatic CYP3A1/2 increase in rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and intestinal CYP3A1/2 enzyme activity decreases in rat model of DMIS. Thus, the pharmacokinetic changes of telithromycin in both models of diabetes mellitus compared with those in the control rats were evaluated. Methods  Telithromycin was administered (50 mg/kg) intravenously or orally to both rat models of diabetes and their respective control rats. Results  After intravenous administration of telithromycin to both models of diabetes, the non-renal clearance (CL_NR) was significantly faster (32.3 and 53.1% increase for rat models of DMIA and DMIS, respectively) and the AUC was significantly smaller (25.0 and 33.8% decrease, respectively) than those in their respective controls. However, after oral administration of telithromycin, the AUC was comparable to that in their respective controls. Conclusions  The faster CL_NR after intravenous administration was due to increased hepatic CYP3A1/2 in both models of diabetes. The comparable AUC after oral administration was mainly due to decreased intestinal CYP3A1/2 activity. Alloxan and streptozotocin appear to influence some pharmacokinetics of telithromycin in a different fashion.     

ϵ-Acetamidocaproic acid pharmacokinetics in rats with gastric ulcer or small bowel inflammation

1. The pharmacokinetics of ?-acetamidocaproic acid (AACA) were evaluated after the intravenous and oral administration of an antiulcer agent, zinc acexamate (ZAC) at a dose of 20?mg kg^?1 (ion pairing between zinc and AACA) in rats with indomethacin-induced acute gastric ulcer (IAGU) or indomethacin-induced small bowel inflammation (ISBI).

2. In IAGU rats, the area under the curves (AUCs) of AACA were significantly smaller after both the intravenous (551 versus 1270 μg min ml^?1) and oral (397 versus 562 μg min ml^?1) administration of ZAC than controls, possible due to the significantly faster CL_R of AACA. In ISBI rats, however, the AUCs of AACA were comparable with controls after both the intravenous and oral administration of ZAC.

3. In IAGU rats, the significantly smaller AUCs of AACA were due to the significantly faster CL_R (due to the decreased urinary pH by indomethacin treatment) than controls. AACA has a basic secondary amine group. On the other hand, the comparable AUCs of AACA in ISBI rats were due to the comparable CL_Rs between ISBI and control rats.

4. AACA was excreted in the urine via active renal tubular secretion in all rats studied.

     

Sources of interindividual variability in IVIVE of clearance: an investigation into the prediction of benzodiazepine clearance using a mechanistic population-based pharmacokinetic model

1. Prediction of metabolic clearance in extreme individuals rather than the ‘average human’ is becoming an attractive tool within the pharmaceutical industry.

2. The current study involved prediction of variability in metabolic clearance for alprazolam, triazolam and midazolam with emphasis on the following factors: first, evaluation of clearance prediction accuracy using intrinsic clearance (CL_int) data from in vitro metabolic data and back-calculation from in vivo clearance data. Second, the sensitivity of predicted in vivo variability to changes in variability for physiological parameters (e.g. liver weight, haematocrit, CYP3A abundance). Finally, reported estimates of variability in hepatic CYP3A4 abundance (coefficient of variation (CV) 95%) were refined by separating experimental from interindividual variability using a repeat measurement protocol in 52 human liver samples.

3. Using in vitro metabolic data, predicted clearances were within 2-fold of observed for triazolam and midazolam. Clearance of alprazolam was overpredicted by 2.0- to 3.7-fold. Use of in vivo CL_int values improved prediction of intravenous clearance to within 2-fold of observed for all drugs.

4. Initially, the variability in clearance was overestimated for all drugs (by 1.8- to 3.6-fold). Use of a reduced hepatic CYP3A4 CV of 41%, representative of interindividual variability alone improved predictions of variability in clearance for all drugs to within 2-fold of observed.

     

Determination of drug-metabolizing enzyme activity in vivo : pharmacokinetic and statistical issues

1. Chlorpyrifos (CPF), an organophosphorus (OP) pesticide, is bioactivated by cytochrome P450s (CYPs) to the active metabolite chlorpyrifos oxon (CPF-O). Given that human CYP2B6 has the highest intrinsic clearance (CL_int) for CPF bioactivation, CYP2B6 polymorphisms may impact human susceptibility to CPF at real world environmental and occupational CPF exposure levels.

2. CYP2B6.4,.5,.7, and .18 were over-expressed in mammalian COS-1 cells to assess the impact of CYP2B6 variants on the K_m and V_max for bioactivation of CPF. Cell lysates were incubated with CPF (0–100 μM) and the production of CPF-O was measured via HPLC analysis. CYP2B6 content was determined by western blot.

3. CYP2B6.18 had neither detectable protein nor activity levels. The V_max value for each remaining variant was significantly higher than wild-type (CYP2B6.1, V_max 4.13?×?10⁴ pmol/min/nmol CYP2B6), with CYP2B6.4,.5, and .7 having V_max values of 4.52?×?10⁵, 1.82?×?10⁵, and 9.60?×?10⁴ pmol/min/nmol CYP2B6, respectively. The K_m values for these variants ranged from 0.39 to 1.09 μM and were not significantly different from wild-type. All active variants examined had significantly higher CL_int than CYP2B6.1.

4. Variants of CYP2B6 have altered capacity to bioactivate CPF and may affect individual susceptibility by altering the V_max for CPF-O formation.

     

Comparison of intrinsic metabolic clearance in fresh and cryopreserved human hepatocytes

1. We compared the intrinsic clearance (CL_int) of a number of substrates in suspensions of fresh and cryopreserved human hepatocytes from seven donors.

2. CL_int values for a cocktail incubation of phenacetin, diclofenac, diazepam, bufuralol, midazolam, and hydroxycoumarin were 4.9?±?3.4, 18?±?7.2, 5.1?±?4.9, 6.3?±?3.3, 9.8?±?5.8 and 22?±?14?μl min^?1/10⁶ cells, respectively, and they correlated well with corresponding CL_int values using cryopreserved hepatocytes from 25 different donors.

3. CL_int values of each cocktail substrate and 20 AstraZeneca new chemical entities were compared in fresh and cryopreserved hepatocytes from the same three donors. There was a statistically significant correlation between CL_int in fresh and cryopreserved hepatocytes for each of the three livers (p?int values was 1.03.

4. In conclusion, the results add further support to the use of cryopreserved human hepatocytes as a screening model for the intrinsic clearance of new chemical entities.

     

Pharmacokinetics of sildenafil and its metabolite,N-desmethylsildenafil,in rats with liver cirrhosis and diabetes mellitus,alone and in combination

1. Pharmacokinetics of sildenafil and its metabolite, N-desmethylsildenafil, in humans and rats with liver cirrhosis (LC) and diabetes mellitus (DM), alone and in combination (LCD) did not seem to be reported.

2. Sildenafil was administered intravenously (10?mg/kg) and orally (20?mg/kg) to control, LC, DM, and LCD rats. Expression of intestinal CYP isozymes in those rats was also measured.

3. In LC, DM, and LCD rats, the areas under the curve (AUCs) of intravenous sildenafil were significantly greater (by 195%, 54.2%, and 127%, respectively) than controls. In LC and LCD rats, AUCs of oral sildenafil were significantly greater (3010% and 2030%, respectively) than controls.

4. In LC, DM, and LCD rats, significantly greater AUCs of intravenous sildenafil were due to the slower hepatic extraction of sildenafil (because of decrease in the protein expression of hepatic CYP2C11 and 3A subfamily in LC and LCD rats, and CYP2C11 in DM rats). In LC and LCD rats, greater magnitude of increase in AUCs of oral sildenafil than those after the intravenous administration could be mainly due to the decrease in the intestinal extraction of sildenafil (because of decrease in the protein expression of intestinal CYP2C11 in LC and LCD rats).

     

Effect of ursodeoxycholic acid on the pharmacokinetics of midazolam and CYP3A in the liver and intestine of rats

1. The elimination half-life of midazolam administered intravenously (5 mg kg^?1) or orally (15 mg kg^?1) was significantly decreased by 70% and 73%, respectively, 24 h after a single oral administration of ursodeoxycholic acid (UDCA, 300 mg kg^?1) in rats. In the liver there was a significant enhancement of the hydroxylation of midazolam in the microsomes and expression of cytochrome P450 (CYP) 3A1 messenger RNA (mRNA) and CYP3A2 mRNA.

2. The C_max and area under the curve (AUC)_0–∞ of midazolam were significantly (1.8–2.3 fold) increased by the single oral treatment with UDCA (100 and 300 mg kg^?1). Thus, the oral bioavailability, estimated from the AUC_0–∞, of midazolam administered intravenously and orally was significantly (1.8- and 2.3-fold, respectively) increased by the treatment with UDCA.

3. Repeated administration of UDCA (300 mg kg^?1 day^?1) for 7 days did not alter the pharmacokinetics of midazolam administered intravenously or orally, and the expression of mRNA for CYP3As in the rat liver.

4. The study has shown that a single administration of UDCA in rats induces significant hepatic CYP3A activity and increases significantly the oral bioavailability of midazolam. Such effects on the pharmacokinetics of midazolam were little observed on the repeated administration of UDCA.

     

Pharmacokinetics of mirodenafil and its two metabolites, SK3541 and SK3544, in spontaneously or DOCA-salt-induced hypertensive rats

Hypertension is the most common comorbidity and major risk factor in patients with erectile dysfunction. The pharmacokinetics of mirodenafil, used for the treatment of erectile dysfunction, after the intravenous and oral administration (20 mg/kg) to 6‐week‐old rats (with blood pressure within the normotensive range) and 16‐week‐old spontaneously hypertensive rats (SHRs) and their age‐matched control normotensive Kyoto–Wistar (KW) rats, and 16‐week‐old deoxycorticosterone acetate–salt‐induced hypertensive rats (DOCA–salt rats) and their age‐matched control Sprague–Dawley (SD) rats were compared. It was found that time‐averaged renal clearance (Cl_r) was of minor importance and that time‐averaged non‐renal clearance (Cl_nr) was dominant. In both 6‐ and 16‐week‐old SHRs, the Cl_nrs and areas under the curve (AUCs) of intravenous mirodenafil were significantly smaller and greater than those of the controls, but in 16‐week‐old DOCA–salt rats, they were comparable to the controls. Although the AUC of oral mirodenafil in 16‐week‐old SHRs was comparable to the controls, the Cl_nrs (or total body clearances, Cls) of intravenous mirodenafil and intestinal intrinsic clearances were significantly smaller than the controls and comparable to the controls for both 6‐ and 16‐week‐old SHRs, unlike in the 16‐week‐old DOCA–salt rats. The above data suggest that the significantly smaller Cl_nr and greater AUC of intravenous mirodenafil and comparable AUC of oral mirodenafil in 16‐week‐old SHR could be due to the hereditary characteristics of SHRs, and not due to the hypertensive state itself. Copyright © 2010 John Wiley & Sons, Ltd.     

Pharmacokinetics of tolbutamide and its metabolite 4‐hydroxy tolbutamide in poloxamer 407‐induced hyperlipidemic rats

Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4‐hydroxy tolbutamide (4‐OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407‐induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration–time curve (AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non‐renal clearance (CL_NR). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4‐hydroxylated metabolite formation ratio (AUC_4‐OHTB/AUC_TB) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CL_int (by 28.8%) for metabolism of tolbutamide to 4‐OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CL_int changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state. Copyright © 2014 John Wiley & Sons, Ltd.     

Effects of Phyllanthus amarus on the pharmacokinetics of midazolam and cytochrome P450 activities in rats

1. Phyllanthus amarus, a commonly used medicinal herb, was investigated for possible herb–drug interactions. The effect on CYP3A-mediated drug metabolism in rats after single dose administration of P. amarus extract was investigated using midazolam (MDZ) as a probe substrate. The effect of multiple dose administration of P. amarus extract on activity and expression of various CYP isoforms were studied.

2. Oral administration of P. amarus extract (800?mg/kg) 1?h before oral MDZ increased the C_max and AUC_0–-∞ of MDZ by 3.9- and 9.6-fold and decreased the clearance by 12%, but did not alter the pharmacokinetics of intravenous MDZ.

3. Daily administration of P. amarus extract (200 or 800?mg/kg/day) for 15 days in rats increased the activity and expression of CYP3A and CYP2B1/2. In contrast, the activities and expressions of CYP1A, CYP2C and CYP2E1 were not significantly changed.

4. The dual effects of P. amarus extract on CYP enzymes were demonstrated. Single dose administration of the extract increased oral bioavailability of MDZ through inhibition of intestinal CYP3A whereas repeated administration of the extract slightly induced hepatic CYP3A and CYP2B1/2 in rats, which suggested that herb–drug interactions by P. amarus may potentially occur via CYP3A and 2B.

     

Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus

Objectives In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration–time curve from time zero to time infinity (AUC) of metabolites, AUC_metabolite/AUC_{parent drug} ratios, or the time‐averaged nonrenal and total body clearances (CL_NR and CL, respectively) of parent drugs as reported in the literature have been compared. Key findings After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in‐vitro hepatic intrinsic clearance (CL_int) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster. Summary Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans.     

Influence of capsaicin on fluctuation of digoxin pharmacokinetics in lipopolysaccharide-treated rats

1. In the present study, we investigated the influence of Cap on digoxin pharmacokinetics in lipopolysaccharide (LPS)-treated rats.

2. After the oral administration of digoxin (0.1?mg/kg), the area under the plasma concentration-time curve (AUC) of digoxin increased significantly until day 3 after LPS treatment. In the LPS + Cap group, the recovery period of AUC was shortened to 3 days. On days 5 and 7, the maximum plasma concentrations decreased significantly as compared to the control group. The bioavailability of digoxin in LPS group was higher than that in the LPS + Cap group.

3. The hepatic cytochrome P450 (CYP) 3A2 content decreased significantly until day 5 after LPS administration, but it returned to the control level until 5 days in the LPS + Cap group. Hepatic CYP3A2 mRNA expression of LPS group decreased significantly until day 3, but it returned to the control level on day 3 and increased significantly until day 7 in the LPS + Cap group.

4. The DNA-binding activity of pregnane X receptor (PXR) was increased on days 3–7 in the Cap and LPS + Cap group.

5. Cap decreased the absorption of digoxin by inducing CYP3A2 mRNA expression via indirect activation of PXR in LPS-treated rats.

     

Separate evaluation of intestinal and hepatic metabolism of three benzodiazepines in rats with cannulated portal and jugular veins: comparison with the profile in non-cannulated mice

1. Pharmacokinetic analyses of three kinds of benzodiazepines—midazolam (MDZ), triazolam (TRZ) and alprezolam (APZ)—were performed in rats with cannulated portal and jugular veins. Each drug was administered to the double-cannulated rats, and pharmacokinetic data for the parent drugs and their 1′- and 4-hydroxylated metabolites were compared with those obtained in non-cannulated mice.

2. In bioavailability, the drugs ranked APZ >> TRZ = MDZ in rats, and APZ > TRZ >> MDZ in mice, with the values for MDZ remarkably different between rats and mice (19% in rats versus 2.3% in mice). In contrast, hepatic availability (F_h) was similar (APZ > TRZ > MDZ) in both species. Highly significant relationships were found between the ratio of the area under the plasma concentration–time curve (AUC) for the parent drugs in portal blood (AUC_por) to that in systemic blood (AUC_sys) and F_h in rats and mice.

3. The double-cannulated rat is useful for estimating the hepatic availability of drug candidates by determining the AUC values for the parent drugs in portal and systemic blood samples.

     

Pharmacokinetics of verapamil and its metabolite norverapamil in rats with hyperlipidaemia induced by poloxamer 407

1. In this study, the pharmacokinetics of verapamil and its active metabolite norverapamil were evaluated following intravenous and oral administration of 10?mg/kg verapamil to rats with hyperlipidaemia (HL) induced by poloxamer 407 (HL rats).

2. The total area under the plasma concentration time curve (AUC) of verapamil in HL rats following intravenous administration was significantly greater (by 11.2%) than in control rats due to their slower (by 11%) non-renal clearance. The oral AUC of verapamil in HL rats was also significantly greater (by 116%) compared with controls, with a larger magnitude than the data observed following intravenous administration. This may have been a result of the decreased intestinal metabolism of verapamil in HL rats.

3. The AUC of norverapamil and AUC_norverapamil/AUC_verapamil ratios following intravenous and oral administration of verapamil were unchanged in HL rats.

4. Assuming that the HL rat model qualitatively reflects similar changes in patients with HL, the findings of this study have potential therapeutic implications. Further studies in humans are required to determine whether modification of the oral verapamil dosage regimen in HL states is necessary.