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).
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 CLR of AACA. In ISBI rats, however, the AUCs of AACA were comparable with controls after both the intravenous and oral administration of ZAC.
In IAGU rats, the significantly smaller AUCs of AACA were due to the significantly faster CLR (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 CLRs between ISBI and control rats.
AACA was excreted in the urine via active renal tubular secretion in all rats studied.
The area under the curve (AUC) of mirodenafil after intravenous administration in diabetes mellitus induced by streptozotocin (DMIS) rats was significantly smaller (by 28.0?%) than the control value, and the AUCSK3541/AUCmirodenafil ratio was significantly greater (by 130?%) in DMIS rats. This may be explained by the significantly faster hepatic CLint of mirodenafil, owing to increased hepatic CYP1A, CYP2B1/2, CYP2D, and CYP3A expression, and a faster hepatic blood flow rate, compared with control values.
The AUC of mirodenafil after oral administration was comparable between DMIS and control rats, possibly because of the comparable intestinal CLint, which may be attributable to increased CYP1A2 expression and decreased CYP2D expression in the intestines of DMIS rats.
After both the intravenous and oral administration of zinc acexamate [ZAC; ion-pairing between zinc and ?-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CLR). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine.
After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone.
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.
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.
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.
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).
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.
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.
In PCM rats, the CLNR (AUC0–∞) 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 CLNR of etoposide in PCM rats was restored to the control level by cysteine treatment. PCMC rats showed a significantly greater AUC0–6 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.
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.
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 (CLint) for compounds with low permeability (<5?×?10?6 cm/s).
We determined apparent uptake CLint by measuring initial disappearance from medium using attached rat hepatocytes and metabolic CLint by measuring parent depletion in suspended rat hepatocytes (cells and medium).
Uptake and metabolic CLint were comparable for highly permeable metabolic marker compounds. In contrast, uptake CLint was 3- to 40-fold higher than metabolic CLint 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.
The prediction of hepatic CL was improved significantly when using uptake CLint for the compounds with low permeability. The average fold error was 2.2 and 6, as opposed to >11 and >47 by metabolic CLint, with and without applying a scaling factor of 4, respectively.
Uptake CLint 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.
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).
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.
The AUC of norverapamil and AUCnorverapamil/AUCverapamil ratios following intravenous and oral administration of verapamil were unchanged in HL rats.
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.
We compared the intrinsic clearance (CLint) of a number of substrates in suspensions of fresh and cryopreserved human hepatocytes from seven donors.
CLint 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 CLint values using cryopreserved hepatocytes from 25 different donors.
CLint 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 CLint in fresh and cryopreserved hepatocytes for each of the three livers (p?int values was 1.03.
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.
Oxidative deamination of the GABAA partial agonist CP-409,092 and sumatriptan represents a major metabolic pathway and seems to play an important role for the clearance of these two compounds.
Similar to sumatriptan, human mitochondrial incubations with deprenyl and clorgyline, probe inhibitors of monoamine oxidase B and monoamine oxidase A (MAO-B and MAO-A), respectively, showed that CP-409,092 was metabolized to a large extent by the enzyme MAO-A.
The metabolism of CP-409,092 and sumatriptan was therefore studied in human liver mitochondria and in vitro intrinsic clearance (CLint) values were determined and compared to the corresponding in vivo oral clearance (CLPO) values. The overall objective was to determine whether an in vitro-in vivo correlation (IVIVC) could be described for compounds cleared by MAO-A.
The intrinsic clearance, CLint, of CP-409,092 was approximately 4-fold greater than that of sumatriptan (CLint, values were calculated as 0.008 and 0.002?ml/mg/min for CP-409,092 and sumatriptan, respectively). A similar correlation was observed from the in vivo metabolic data where the unbound oral clearance, CL(u)PO, values in humans were calculated as 724 and 178?ml/min/kg for CP-409,092 and sumatriptan, respectively.
The present work demonstrates that it is possible to predict in vivo metabolic clearance from in vitro metabolic data for drugs metabolized by the enzyme monoamine oxidase.
The objective of this study is to report the effects of cysteine on the pharmacokinetics of intravenous and oral docetaxel in rats with protein–calorie malnutrition (PCM). The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of docetaxel were assessed using control, CC (control with cysteine), PCM and PCMC (PCM with cysteine) rats. The effects of cysteine on the intestinal absorption of docetaxel were further investigated through in vitro transport studies using rat intestine and Caco-2 cell monolayers.
The AUCs (the areas under the plasma concentration-time curve from time zero to time infinity) of intravenous docetaxel in PCM rats were significantly greater than in the control rats because of the significant decrease in the hepatic CYP3A. In PCMC rats, the elevated AUCs in PCM rats returned to control levels. The AUC0–6 hs of oral docetaxel in PCM rats were significantly smaller than that in the control rats, mainly due to the decrease in gastrointestinal absorption. In CC and PCMC rats, oral cysteine supplement enhanced the gastrointestinal absorption of docetaxel probably via intestinal P-gp inhibition.
If the present rat data could be expressed to humans, the alterations in docetaxel absorption and metabolism should be considered in designing a dosage regimen for cancer patients with PCM state after cysteine supplement.
Identifying kinetic determinants of hepatic elimination of drugs would be crucial for better understanding its pharmacokinetics and predicting drug interactions. Present study investigated the kinetics of sinusoidal uptake of docetaxel and its impact on the overall hepatic elimination of docetaxel in rats.
The non-renal clearance (CLNR; hepatic elimination) of docetaxel were significantly reduced by co-administration of intravenous rifampicin, a potent inhibitor of organic anion transporting peptides (OATPs; Oatps), at a dose of 20?mg/kg. Docetaxel uptake into isolated rat hepatocytes was found to be temperature/concentration/energy-dependent, saturable, and reduced by Oatps inhibitors (rifampicin and bromosulfophthalein). Moreover, docetaxel uptake into perfused rat liver was significantly reduced in the presence of 10-µM rifampicin. However, docetaxel metabolism in rat hepatic microsome was not affected by rifampicin at less than 50 µM.
Based on the comparison of intrinsic clearances related to hepatic clearance, it can be suggested that sinusoidal uptake could be the rate-determining process in the overall hepatic elimination of docetaxel in rats.
Prediction of metabolic clearance in extreme individuals rather than the ‘average human’ is becoming an attractive tool within the pharmaceutical industry.
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 (CLint) 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.
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 CLint values improved prediction of intravenous clearance to within 2-fold of observed for all drugs.
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.
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.
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.
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 AUCM1, 0?8 h/AUCLQ and AUCM2, 0?8 h/AUCLQ 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.
Modification of oral dosage regimen of LQ may not be necessary in patients with acute hepatitis; but human studies are required.
下载免费PDF全文 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.
Total body clearance (CLtotal) for female rats was around one-sixth of that for male rats. In vivo hepatic clearance (CLh) calculated based on isolated liver perfusion studies was even higher than or around 90% of the in vivo CLtotal of cilostazol for female and male rats, respectively, indicating that cilostazol is mainly eliminated by the liver in both male and female rats.
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.
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.
BACKGROUND AND PURPOSE
Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats.EXPERIMENTAL APPROACH
Itraconazole (20 mg·kg−1) and metformin (100 mg·kg−1) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (Vmax), Michaelis–Menten constant (Km) and intrinsic clearance (CLint) for the disappearance of each drug, apparent inhibition constant (Ki) and [I]/Ki ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro.KEY RESULTS
After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration–time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes.CONCLUSIONS AND IMPLICATIONS
The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2. 相似文献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.
Oral administration of P. amarus extract (800?mg/kg) 1?h before oral MDZ increased the Cmax and AUC0–-∞ of MDZ by 3.9- and 9.6-fold and decreased the clearance by 12%, but did not alter the pharmacokinetics of intravenous MDZ.
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.
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.
The effects of folic acid-induced acute renal failure on the renal excretion of belotecan were investigated in rats after intravenous administration.
Both glomeruli and renal tubules were seriously damaged by folic acid-induced acute renal failure. The renal excretion clearance, CLr, of belotecan was significantly decreased by folic acid-induced acute renal failure. Furthermore, glomerular filtration rate and secretion clearance of the drug were dramatically decreased by folic acid-induced acute renal failure.
In vivo renal uptake of belotecan was inhibited by p-aminohippurate, whereas renal excretion was inhibited by GF120918, but not by verapamil and bromosulphalein. This indicates that Oat1/3 and Bcrp are involved in the renal uptake and urinary excretion of belotecan, respectively.
Both mRNA and protein levels of Oat1, Oat3 and Bcrp were significantly decreased in folic acid-induced acute renal failure rats. Based on the finding that belotecan is a substrate of OAT1 but not of OAT3, the decrease in CLr of belotecan in folic acid-induced acute renal failure could, therefore, mainly be attributed to the down-regulation of Oat1 and Bcrp, in addition to the decrease in glomerular filtration rate.
The metabolism and excretion of a GABAA partial agonist developed for the treatment of anxiety, CP-409,092; 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (4-methylaminomethyl-phenyl)-amide, were studied in rats following intravenous and oral administration of a single doses of [14C]CP-409,092.
The pharmacokinetics of CP-409,092 following single intravenous and oral doses of 4 and 15?mg kg?1, respectively, were characterized by high clearance of 169?±?18?ml min?1 kg?1, a volume of distribution of 8.99?±?1.46 l kg?1, and an oral bioavailability of 2.9% ± 3%.
Following oral administration of 100?mg kg?1 [14C]CP-409,092, the total recovery was 89.1% ± 3.2% for male rats and 89.3% ± 0.58% for female rats. Approximately 87% of the radioactivity recovered in urine and faeces were excreted in the first 48?h. A substantial portion of the radioactivity was measured in the faeces as unchanged drug, suggesting poor absorption and/or biliary excretion. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or faeces.
The major metabolic pathways of CP-409,092 were hydroxylation(s) at the oxo-tetrahydro-indole moiety and oxidative deamination to form an aldehyde intermediate and subsequent oxidation to form the benzoic acid. The minor metabolic pathways included N-demethylation and subsequent N-acetylation and oxidation.
The present work demonstrates that oxidative deamination at the benzylic amine of CP-409,092 and subsequent oxidation to form the acid metabolite seem to play an important role in the metabolism of the drug, and they contribute to its oral clearance and low exposure.