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Intestinal Metabolism (intestinal + metabolism)
Selected AbstractsIn Vivo use of the P450 inactivator 1-aminobenzotriazole in the rat: Varied dosing route to elucidate gut and liver contributions to first-pass and systemic clearanceJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 6 2006Timothy J. Strelevitz Abstract The small intestine is regarded as an absorptive organ in the uptake of orally administered drugs, but also has the ability to metabolize drugs by both phase 1 and phase 2 reactions. The amount of drug that reaches the systemic circulation can be reduced by both intestinal and hepatic metabolism. 1-Aminobenzotriazole (ABT) is an irreversible inhibitor of cytochrome P450s. Through in vivo and in vitro studies, ABT has been evaluated for its utility in studying intestinal metabolism in rats. Rats have been exposed to ABT through varied routes of administration followed by p.o. and i.v. administration of midazolam (MDZ), a CYP3A substrate. The MDZ bioavailablity in rats dosed orally and in rats dosed intravenously with ABT is 58.5% and 0.7%, respectively (%F,=,2.3% w/o ABT). The approximately 80-fold difference between the two groups suggests the majority of the extraction occurs in the intestine following an oral dose. To further study the utility of ABT, the antihistamine fexofenadine (Fex), which is not significantly metabolized and is a substrate for the uptake and efflux transporters, OATP and P-gp, was tested in rat. There was no change in oral or systemic exposure of Fex when animals were predosed with ABT, suggesting that ABT does not affect these transporters. These findings may lead to a better understanding of the interdependent role of absorption and metabolism and the specificity of ABT. This method should have utility in drug discovery for the identification of factors limiting oral bioavailability. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95:1334,1341, 2006 [source] Effect of recombinant porcine somatotropin (rpST) on drug disposition in swineJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010J. C. KAWALEK Kawalek, J.C., Howard, K.D. Effect of recombinant porcine somatotropin (rpST) on drug disposition in swine. J. vet. Pharmacol. Therap.33, 69,75. Treatment of pigs with recombinant porcine somatotropin (rpST) causes a marked increase in feed utilization with increased weight-gain over untreated controls. Physiological parameters such as creatinine clearance were increased by rpST treatment. Clearance of drugs eliminated by hepatic extraction, like indocyanine green (ICG), were also increased by rpST treatment. However, clearance of intravenous (i.v.)-dosed propranolol (PPL) was not affected by rpST treatment and data from oral (p.o.) - dosing was inconclusive because of the low bioavailability, probably because of a high first-pass effect. The very low oral bioavailability indicates that intestinal metabolism of PPL is probably quite high. Analysis of urinary metabolites indicated production of the two phenolic isomers, but there was no metabolite corresponding to N-dealkylase activity; although the latter metabolite could have been eliminated in the bile with subsequent fecal elimination. PPL was an excellent in vitro substrate for measuring hepatic DME activity in vitro; two phenolic and one N-dealkylated metabolite were formed. The overall conclusions regarding this study must be that the effects of rpST on drug bioavailability and elimination were equivocal. As ICG and creatinine clearances were both increased significantly, one cannot rule out the probability that rpST would increase drug elimination in pigs as a result of increased hepatic uptake and/or renal clearance. One can only speculate that clearance of concurrently administered drugs would be increased. This would reduce residue levels, but it might also reduce efficacy. [source] Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2009Avantika Barve Abstract The purpose of this study was to compare the hepatic and small intestinal metabolism, and to examine bioavailability and gastro-intestinal first-pass effects, of kaempferol in rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of kaempferol for up to 120,min. Based on the values of the kinetic constants (Km and Vmax), the propensity for UDPGA-dependent conjugation compared with NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered kaempferol intravenously (i.v.) (10, 25,mg/kg) or orally (100, 250,mg/kg). Gastro-intestinal first-pass effects were observed by collecting portal blood after oral administration of 100,mg/kg kaempferol. Pharmacokinetic parameters were obtained by non-compartmental analysis using WinNonlin. After i.v. administration, the plasma concentration,time profiles for 10 and 25,mg/kg were consistent with high clearance (,3,L/hr/kg) and large volumes of distribution (8,12,L/hr/kg). The disposition was characterized by a terminal half-life value of 3,4,h. After oral administration the plasma concentration,time profiles demonstrated fairly rapid absorption (tmax,1,2,h). The area under the curve (AUC) values after i.v. and oral doses increased approximately proportional to the dose. The bioavailability (F) was poor at ,2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver. Copyright © 2009 John Wiley & Sons, Ltd. [source] Ipriflavone pharmacokinetics in mutant Nagase analbuminemic ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2009Hye J. Chung Abstract Ipriflavone, a derivative of naturally occurring isoflavones, was primarily metabolized in rats via hepatic CYP1A1/2 and 2C11. Protein and mRNA expression of CYP1A2 in the liver, reported to be increased in mutant Nagase analbuminemic rats (NARs), should influence the pharmacokinetic parameters of ipriflavone. In this study, the contribution of hepatic CYP2C11 and intestinal CYP1A protein to the metabolism and the pharmacokinetic parameters of ipriflavone were examined after intravenous (20,mg/kg) and oral (200,mg/kg) administration to male Sprague,Dawley (control) rats and NARs. There was no change in the protein expression of hepatic CYP2C11. By contrast, CYP1A protein of the intestine increased by almost 100%. After the intravenous administration of ipriflavone to NARs, the Clnr and AUC were unchanged, suggesting that the contribution of the increase in protein expression and mRNA level of hepatic CYP1A2 to hepatic metabolism of the drug in NARs seemed to be almost negligible. However, after the oral administration of ipriflavone to NARs, the AUC was significantly lower than that in the control rats (53.0% decrease), possibly due to the increased intestinal CYP1A that resulted in increased intestinal metabolism and decreased gastrointestinal absorption of ipriflavone in NARs. Copyright © 2009 John Wiley & Sons, Ltd. [source] Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein bindingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2009Dae Y. Lee Abstract 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 Clnr 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. [source] Gender differences in ondansetron pharmacokinetics in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2008Si H. Yang Abstract It has been reported that ondansetron is primarily metabolized via hepatic CYP2D and 3A1/2 in male Sprague,Dawley rats, and CYP2D1 and 3A2 are male dominant and male specific isozymes, respectively, in rats. Thus, it could be expected that the pharmacokinetics of ondansetron would be changed in male rats compared with those in female rats. Thus, gender-different ondansetron pharmacokinetics were evaluated after its intravenous or oral administration at a dose of 8 mg/kg to male and female Sprague,Dawley rats. After intravenous administration of ondansetron to male rats, the AUC and time-averaged non-renal clearance (Clnr) of the drug were significantly smaller (22.6% decrease) and faster (27.3% increase), respectively, than those in female rats. This probably could be due to faster hepatic blood flow rate in male rats. After oral administration of ondansetron to male rats, the AUC of the drug was also significantly smaller (58.8% decrease) than that in female rats, and this could have been due mainly to increased intestinal metabolism of ondansetron in addition to increased hepatic metabolism of the drug in male rats. Copyright © 2008 John Wiley & Sons, Ltd. [source] In Vitro/in Vivo scaling of alprazolam metabolism by CYP3A4 and CYP3A5 in humansBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2001Noriko Hirota Abstract We attempted to predict the in vivo metabolic clearance of alprazolam from in vitro metabolic studies using human liver microsomes and human CYP recombinants. Good correlations were observed between the intrinsic clearance (CLint) for 4-hydroxylation and CYP3A4 content and between the CLint for ,-hydroxylation and CYP3A5 content in ten human liver microsomal samples. Using the recombinant CYP isoforms expressed in insect cells, the CLint for CYP3A4 was about 2-fold higher than the CLint for CYP3A5 in the case of 4-hydroxylation. However, the CLint for CYP3A5 was about 3-fold higher than the CLint for CYP3A4 in the case of ,-hydroxylation. The metabolic rates for 4- and ,-hydroxylation increased as the added amount of cytochrome b5 increased, and their maximum values were 3- to 4-fold higher than those without cytochrome b5. The values of CLint, in vivo predicted from in vitro studies using human liver microsomes and CYP3A4 and CYP3A5 recombinants were within 2.5 times of the observed value calculated from literature data. The average CLint value (sum of 4- and ,-hydroxylation) obtained using three human liver microsomal samples was 4-fold higher than that obtained using three small intestinal microsomal samples from the same donors, indicating the minor contribution of intestinal metabolism to alprazolam disposition. The area under the plasma concentration-time curve (AUC) of alprazolam is reported to increase following co-administration of ketoconazole and the magnitude of the increase predicted from the in vitroKi values and reported pharmacokinetic parameters of ketoconazole was 2.30,2.45, which is close to the value observed in vivo (3.19). A quantitative prediction of the AUC increase by cimetidine was also successful (1.73,1.79 vs 1.58,1.64), considering the active transport of cimetidine into the liver. In conclusion, we have succeeded in carrying out an in vitro/in vivo scaling of alprazolam metabolism using human liver microsomes and human CYP3A4 and CYP3A5 recombinants. Copyright © 2001 John Wiley & Sons, Ltd. [source] Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8*2 variant alleleBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2010Jean-Baptiste Woillard WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Mycophenolate mofetil (MMF), the most widely used drug in allograft transplantation, is subject to hepatic and intestinal glucuronidation and entero-hepatic cycling. , Diarrhoea is its most frequent adverse event leading to non-compliance, treatment interruption and ultimately to an increased rate of acute rejection. , Cyclosporin reduces the biliary excretion of mycophenolate metabolites, presumably by inhibiting the efflux transporter MRP2. , When combined with MMF, cyclosporin reduces the incidence of diarrhoea, suggesting the role played by biliary excretion of mycophenolate glucuronides in this adverse event. WHAT THIS STUDY ADDS , In a long-term cohort of renal transplant patients on MMF, the two factors significantly associated with a reduced incidence of diarrhoea were the co-medication with cyclosporin (as opposed to tacrolimus or sirolimus) and the *2 variant allele of the intestinal UGT1A8. , Polymorphisms in the other UDP-glucuronosyl-transferases and MRP2 were not significant. AIM In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites. METHODS Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (*2; 518C>G, *3; 830G>A), UGT1A7 (622C>T), UGT1A9 (,275T>A), UGT2B7 (,840G>A) and ABCC2 (,24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model. RESULTS Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8*2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8*2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331). CONCLUSION These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8*2 carriers may be protective factors against MMF-induced diarrhoea. [source] Effect of bile and lipids on the stereoselective metabolism of halofantrine by rat everted-intestinal sacsCHIRALITY, Issue 2 2010Jigar P. Patel Abstract The everted rat intestinal-sac model was utilized to assess the effect of post-prandial conditions on the stereoselective intestinal metabolism of halofantrine to its active metabolite desbutylhalofantrine. Everted intestinal sacs were incubated with (±)-halofantrine HCl in the presence of simulated bile solution (containing lecithin, lipase and cholesterol) and lipids to mimic post-prandial conditions in the small intestine. The halofantrine enantiomer concentrations in intestinal sacs were relatively constant in the presence of bile, but decreased significantly on addition of lipids to the incubation media. Formation of desbutylhalofantrine enantiomers was inversely proportional to bile concentration whereas addition of lipids in the presence of bile caused a significant decrease in desbutylhalofantrine:halofantrine ratio of (,) enantiomers. Pre-treatment of rats with peanut oil had no significant effect on desbutylhalofantrine formation in the incubated sacs or microsomal preparations, nor did it affect the expression of intestinal cytochrome P450. Addition of extra cholesterol to the bile incubations caused a significant increase in tissue halofantrine and desbutylhalofantrine concentrations, which as for lower cholesterol, were diminished on addition of other lipids. The results were consistent with previous in vivo evaluations showing that the desbutylhalofantrine to halofantrine ratio was decreased by the ingestion of a high fat meal. Chirality, 2010. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||