Intestinal First-pass Effect Research Articles

Pharmacokinetics and extensive intestinal first-pass effects of apigenin and its active metabolite, apigenin-7-O-glucuronide, in rats

Pharmacokinetics and extensive intestinal first-pass effects of apigenin and its active metabolite, apigenin-7-O-glucuronide, in rats

Integrated Use of In Vitro and In Vivo Information for Comprehensive Prediction of Drug Interactions Due to Inhibition of Multiple CYP Isoenzymes.

Mechanistic static pharmacokinetic (MSPK) models are simple, have fewer data requirements, and have broader applicability; however, they cannot use in vitro information and cannot distinguish the contributions of multiple cytochrome P450 (CYP) isoenzymes and the hepatic and intestinal first-pass effects appropriately. We aimed to establish a new MSPK analysis framework for the comprehensive prediction of drug interactions (DIs) to overcome these disadvantages. Drug interactions that occurred by inhibiting CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in the liver and CYP3A in the intestine were simultaneously analyzed for 59 substrates and 35 inhibitors. As in vivo information, the observed changes in the area under the concentration-time curve (AUC) and elimination half-life (t1/2), hepatic availability, and urinary excretion ratio were used. As in vitro information, the fraction metabolized (fm) and the inhibition constant (Ki) were used. The contribution ratio (CR) and inhibition ratio (IR) for multiple clearance pathways and hypothetical volume (VHyp) were inferred using the Markov Chain Monte Carlo (MCMC) method. Using in vivo information from 239 combinations and in vitro 172 fm and 344 Ki values, changes in AUC, and t1/2 were estimated for all 2065 combinations, wherein the AUC was estimated to be more than doubled for 602 combinations. Intake-dependent selective intestinal CYP3A inhibition by grapefruit juice has been suggested. By separating the intestinal contributions, DIs after intravenous dosing were also appropriately inferred. This framework would be a powerful tool for the reasonable management of various DIs based on all available in vitro and in vivo information.

Enhanced bioavailability and hepatoprotective effect of silymarin by preparing silymarin-loaded solid dispersion formulation using freeze-drying method.

This study aimed to develop a solid dispersion formulation of silymarin (Silymarin-SD) using freeze-drying method to enhance its oral bioavailability (BA) by inhibiting the intestinal first-pass effect and increasing its solubility and permeability. Silymarin-SD formulation (i.e., silymarin:tween 80:hydroxypropyl cellulose (HPC) = 1:1:3 (w/w/w) significantly increased silymarin permeability in the duodenum, jejunum, and ileum by decreasing the efflux ratio of silymarin and by inhibiting silymarin-glucuronidation activity, in which tween 80 played a crucial role. As a result, orally administered Silymarin-SD formulation increased plasma silymarin concentrations and decreased silymarin-glucuronide in rats compared with silymarin alone and silymmarin:D-α-tocopherol polyethylene glycol 1000 succinate (1:1, w/w) formulation. In addition to modulating intestinal first-pass effect, Silymarin-SD formulation showed a significantly higher cumulative dissolution for 120min compared with that of silymarin from the physical mixture (PM) of the same composition as Silymarin-SD and silymarin alone; the relative BA of silymarin-SD increased to 215% and 589% compared with silymarin-PM and silymarin alone, respectively. This could be attributed to the amorphous status of the Silymarin-SD formulation without chemical interaction with excipients, such as tween 80 and HPC. Moreover, the hepatoprotective effect of Silymarin-SD in acetaminophen-induced acute hepatotoxicity, as estimated from the alanine aminotransferase and aspartate aminotransferase values, was superior to that of silymarin. In conclusion, the increase in the dissolution rate and intestinal permeability of silymarin, and the inhibition of silymarin-glucuronidation by the Silymarin-SD formulation, prepared using tween 80 and HPC, increased its plasma concentration and resulted in a superior hepatoprotective effect compared to silymarin.

Pharmacokinetic assessment of hepatic and intestinal first-pass effect of S-adenosylmethionine in rats

Pharmacokinetic assessment of hepatic and intestinal first-pass effect of S-adenosylmethionine in rats

Species-dependent hepatic and intestinal metabolism of selective estrogen receptor degrader LSZ102 by sulfation and glucuronidation

1. LSZ102 is an orally bioavailable selective estrogen receptor degrader in clinical development for the treatment of breast cancer. Preclinical studies showed efficacy in xenograft models on oral dosing. However, oral bioavailability was relatively low in several preclinical species (7-33%), and was associated with first-pass metabolism, particularly intestinal first-pass. 2. To investigate metabolism and first-pass effects, metabolites were analysed in human plasma samples after oral dosing of LSZ102 to patients, rat plasma samples after oral dosing of [14C]LSZ102, and in vitro incubations of [14C]LSZ102 with human and rat hepatocytes and intestinal S9 fractions. The kinetics of human sulfotransferase enzymes potentially involved in metabolism of LSZ102 were characterized. 3. Sulfate metabolites were found to be the major components in human plasma, as well as in human hepatocytes and intestinal S9 fractions. Contrastingly, glucuronidation was predominant in rat plasma, hepatocytes and intestinal S9. LSZ102 was found to be metabolized by several human sulfotransferases expressed in liver and intestine. The combined metabolism data in rat and human provide supporting evidence for an extensive intestinal first-pass metabolism effect via sulfation in human but glucuronidation in rat. 4. As LSZ102 is metabolized by a number of different sulfotransferases, drug-drug interactions resulting from the inhibition of one sulfotransferase are unlikely. 5. Despite the observed species difference in metabolism, the major human metabolites of LSZ102, sulfate M5, glucuronide M4, and secondary glucuronide/sulfate metabolite M12, have no or weak pharmacological activity and are not considered a toxicity risk as they are phase II conjugative metabolites.

Oleacein Intestinal Permeation and Metabolism in Rats Using an In Situ Perfusion Technique.

Oleacein (OLEA) is one of the most important phenolic compounds in extra virgin olive oil in terms of concentration and health-promoting properties, yet there are insufficient data on its absorption and metabolism. Several non-human models have been developed to assess the intestinal permeability of drugs, among them, single-pass intestinal perfusion (SPIP), which is commonly used to investigate the trans-membrane transport of drugs in situ. In this study, the SPIP model and simultaneous luminal blood sampling were used to study the absorption and metabolism of OLEA in rats. Samples of intestinal fluid and mesenteric blood were taken at different times and the ileum segment was excised at the end of the experiment for analysis by LC–ESI–LTQ–Orbitrap–MS. OLEA was mostly metabolized by phase I reactions, undergoing hydrolysis and oxidation, and metabolite levels were much higher in the plasma than in the lumen. The large number of metabolites identified and their relatively high abundance indicates an important intestinal first-pass effect during absorption. According to the results, OLEA is well absorbed in the intestine, with an intestinal permeability similar to that of the highly permeable model compound naproxen. No significant differences were found in the percentage of absorbed OLEA and naproxen (48.98 ± 12.27% and 43.96 ± 7.58%, respectively).

Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal absorption of octreotide in rats with portal hypertension

BackgroundPortal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination.MethodsThe bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed.ResultsBoth in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption.ConclusionsInhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.

Auto-Induction of Intestinal First-Pass Effect Related Time-Dependent Pharmacokinetics of Artemisinin Rather than Dihydroartemisinin

Artemisinin (ART) drugs showed declining plasma concentrations after repeated oral dosing, known as time-dependent pharmacokinetics (PK). ART and dihydroartemisinin (DHA) were adopted as representatives to evaluate the roles of first-pass effects and systemic metabolism in time-dependent PK by comparison of oral versus intravenous administration and 1 dose versus 5 consecutive doses PK in rats and dogs, respectively. The hepatic extraction ratio (ERh) and the intestinal elimination changes were further investigated in rats to distinguish the roles of hepatic first-pass effect or intestinal first-pass effect. The induction capacities of ARTs to cytochrome P450 (CYP450) in rats and human cells were evaluated as well. For ART, only the oral groups showed time-dependent PK. A fairly high ERh that obtained for ART was not sensitive to multiple oral doses. An increased elimination and CYP450 expression have also been found in the intestine. For DHA, though a significant CYP450 induction was observed, neither time-dependent PK nor changes in the first-pass effects was found. In conclusion, time-dependent PK of ART was mainly caused by the increased intestinal first-pass effect rather than hepatic first-pass effect or systemic metabolism. DHA was not involved in auto-induction elimination, thus showing no time-dependent PK.

Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation

We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the potential to inhibit P-gp and cytochrome P450s (i.e., CYP1A2, 2C9, 2C19, 2D6, and 3A4). A berberine-loaded mixed micelle formulation with ratios of berberine: P85: tween 80 of 1:5:0.5 (w/w/w) was developed. This berberine mixed micelle formulation had a mean size of 12 nm and increased the cellular accumulation of digoxin via P-gp inhibition. It also inhibited berberine metabolism in rat intestinal microsomes, without significant cytotoxicity, up to a berberine concentration of 100 μM. Next, we compared the pharmacokinetics of berberine and its major metabolites in rat plasma following the oral administration of the berberine formulation (50 mg/kg) in rats with the oral administration of berberine alone (50 mg/kg). The plasma exposure of berberine was significantly greater in rats administered the berberine formulation compared to rats administered only berberine, which could be attributed to the increased berberine absorption by inhibiting the P-gp-mediated berberine efflux and intestinal berberine metabolism by berberine formulation. In conclusion, we successfully prepared berberine mixed micelle formulation using P85 and tween 80 that has inhibitory potential for P-gp and CYPs (CYP2C19, 2D6, and 3A4) and increased the berberine plasma exposure. Therefore, a mixed micelle formulation strategy with P85 and tween 80 for drugs with high intestinal first-pass effects could be applied to increase the oral absorption and plasma concentrations of the drugs.

Successful Prediction of Human Pharmacokinetics After Oral Administration by Optimized Physiologically Based Pharmacokinetics Approach and Permeation Assay Using Human Induced Pluripotent Stem Cell–Derived Intestinal Epithelial Cells

None of the physiologically based pharmacokinetic (PBPK) approaches using preclinical data show high predictability of human pharmacokinetic (PK) profiles for drugs affected by the intestinal first-pass effect. Here we report a novel PBPK approach that incorporated the findings of a permeation study using human induced pluripotent stem cell-derived intestinal epithelial cells (hiPSC-IECs) to predict human PK profiles after oral administration of drugs. In hiPSC-IECs, gene expression levels of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) are enhanced by rifampicin and 1,25-dihydroxyvitamin D3. The permeability of 24 drugs (10 test drugs and 14 reference drugs), including CYP3A4 and P-gp substrates, correlated highly with gastrointestinal availability (Fa × Fg), and could be converted to the apparent absorption rate constant (ka, app) based on the correlation between Fa × Fg and in vivo ka of 27 drugs. The ka, app was input into the PBPK model which contained the optimized calculation processes of metabolism and tissue distribution. The absolute average fold error of PK parameters such as maximum plasma concentration and bioavailability for test drugs was less than 2, suggesting that human PK profiles could be predicted with high accuracy. Our robust PBPK approach enables quick decision-making in drug discovery based on human PK profiles.

Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Intestinal First-Pass Metabolism.

This study investigated the pharmacokinetics of tofacitinib in rats and the effects of first-pass metabolism on tofacitinib pharmacokinetics. Intravenous administration of 5, 10, 20, and 50 mg/kg tofacitinib showed that the dose-normalized area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly higher at 50 mg/kg than at lower doses, a difference possibly due to saturation of the hepatic metabolism of tofacitinib. Oral administration of 10, 20, 50, and 100 mg/kg tofacitinib showed that the dose-normalized AUC was significantly higher at 100 mg/kg than at lower doses, a difference possibly due to saturation of the intestinal metabolism of tofacitinib. Following oral administration of 10 mg/kg tofacitinib, the unabsorbed fraction from the rat intestine was 3.16% and the bioavailability (F) was 29.1%. The AUC was significantly lower (49.3%) after intraduodenal, compared to intraportal, administration, but did not differ between intragastric and intraduodenal administration, suggesting that approximately 46.1% of orally administered tofacitinib was metabolized through an intestinal first-pass effect. The AUC was also significantly lower (42%) after intraportal, compared to intravenous, administration, suggesting that the hepatic first-pass effect on tofacitinib after entering the portal vein was approximately 21.3% of the oral dose. Taken together, these findings suggest that the low F of tofacitinib is due primarily to intestinal first-pass metabolism.

Investigating the bioavailabilities of olerciamide A via the rat's hepatic, gastric and intestinal first-pass effect models.

Olerciamide A (OA) is a new alkaloid isolated from Portulaca oleracea L. that has been proved to possess a low bioavailability (F) after oral administration in rats in our previous study. Hence, to clarify the reasons for its low bioavailability, hepatic, gastric and intestinal first-pass effect models were established, and a rapid, sensitive UHPLC method was validated and applied for the determination after dosing via the femoral, portal, gastric and intestinal routes. As inhibitors of CYP3A and P-gp, verapamil, midazolam and borneol in low and high dose groups were selected to improve the low bioavailability of olerciamide A. Moreover, a rectal administration method was also carried out to improve the bioavailability of olerciamide A. The results showed that the bioavailability of olerciamide A using hepatic, gastric and intestinal routes were 92.16%, 84.88% and 5.76%, respectively. The areas under the plasma concentration-time curve from zero to infinity (AUC0 → ∞ ) were increased a little after being dosed with 10 and 30mg/kg verapamil (p>0.05), but markedly increased after being dosed with 0.4 and 1.2mg/kg midazolam as well as 8 and 24mg/kg borneol (p<0.05). Besides, the AUC0→∞ values after the lower and upper rectal administrations were separately similar to the intravenous and intraportal administrations. Our study showed that the intestinal first-pass effect mainly contributed to the low bioavailability of olerciamide A in rats due to it being a substrate of CYP3A and P-gp as well as to its poor intestinal absorption.

Generation of Human iPSC–Derived Intestinal Epithelial Cell Monolayers by CDX2 Transduction

Background & aimsTo develop an effective and safe orally administered drug, it is important to predict its intestinal absorption rate, intestinal first-pass effect, and drug-drug interactions of orally administered drugs. However, there is no existing model to comprehensively predict the intestinal pharmacokinetics and drug-response of orally administered drugs. In this study, we attempted to generate homogenous and functional intestinal epithelial cells from human induced pluripotent stem (iPS) cells for pharmaceutical research.MethodsWe generated almost-homogenous Villin- and zonula occludens-1 (ZO1)-positive intestinal epithelial cells by caudal-related homeobox transcription factor 2 (CDX2) transduction into human iPS cell-derived intestinal progenitor cells.ResultsThe drug absorption rates in human iPS cell-derived intestinal epithelial cell monolayers (iPS-IECM) were highly correlated with those in humans (R2=0.91). The expression levels of cytochrome P450 (CYP) 3A4, a dominant drug-metabolizing enzyme in the small intestine, in human iPS-IECM were similar to those in human small intestine in vivo. In addition, intestinal availability in human iPS-IECM (the fraction passing the gut wall: Fg=0.73) was more similar to that in the human small intestine in vivo (Fg=0.57) than to that in Caco-2 cells (Fg=0.99), a human colorectal adenocarcinoma cell line. Moreover, the drug-drug interaction and drug-food interaction could be observed by using our human iPS-IECM in the presence of an inducer and inhibitor of CYP3A4, i.e., rifampicin and grape fruit juice, respectively.ConclusionTaking these results together, we succeeded in generating the human iPS-IECM that can be applied to various intestinal pharmacokinetics and drug-response tests of orally administered drugs.

Intestinal absorption and activation of decitabine amino acid ester prodrugs mediated by peptide transporter PEPT1 and enterocyte enzymes

Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5′-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in Peff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic Km: 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes.

Absorption, liver first-pass effect, pharmacokinetics and tissue distribution of calycosin-7-O-ß-d-glucopyranoside (C7G) and its major active metabolite, calycosin, following oral administration of C7G in rats by LC–MS/MS

Previously, we discovered calycosin, an extensively distributed metabolite of Calycosin-7-O-ß-d-glucopyranoside (C7G), elicited stronger anti-virus activity than C7G. However, the pharmacokinetics and tissue distribution of C7G and calycosin remained obscure on C7G treatments. In this study, a liquid chromatography–tandem mass spectrometry method was established and validated for the simultaneous determination of C7G and calycosin, and it was applied to the pharmacokinetics and tissue distribution of C7G and calycosin following oral administration of C7G at 120mg/kg in rats. Consequently, the exposure of C7G and calycosin was both similarly low in the systemic plasma, but the levels of calycosin were 53.5 folds higher than that of C7G in the portal vein plasma, corresponding to the liver extraction ratio (ER) of C7G and calycosin at 0.3% and 98.5% respectively. Therefore, our results revealed that liver first-pass effect played the predominant role in the poor circulating levels of calycosin on C7G treatments, whereas the intestinal first-pass effect was predominant for those of C7G. In contrast to no observation of C7G, the calycosin levels were 212.1, 30.5 and 4.7 folds higher in the liver, kidney and heart than its circulating levels, respectively. The high tissue distribution of calycosin provided new hints and evidences to the pharmacological mechanisms of C7G and Astragali Radix.

Involvement of intestinal efflux and metabolic instability in the pharmacokinetics of platycodin D in rats

We aimed to investigate the underlying mechanisms for low bioavailability of Platycodin D (PD) in rats. The bioavailability of PD was 1.89% with different half-lives depending on the administration route (2.14 ± 0.18 h for intravenous injection vs 5.42 ± 1.9 h for oral administration). The mean absorption time was 6.3 h calculated from the mean residence time of both administration routes. Consistent with these parameters, rat intestinal permeability using 3 different intestinal segments showed a low but greatest permeability in lower ileum (0.05 × 10−6 cm/s in jejunum and upper ileum vs 0.13 × 10−6 cm/s in lower ileum). The involvement of efflux system, probably Mrps, in upper ileum, could be explained from the efflux ratio of 6.4 and reduced efflux ratio by an Mrp inhibitor, MK571. The recovery of unchanged PD after the intravenous and oral administration was 50% and 5.2%, respectively, suggesting the contribution of gastrointestinal metabolism. In the gastrointestinal content, 4 metabolites of PD were identified: acetylated PD (m/z 1265.6), deglucose PD (m/z 1061.5), deapiose PD (m/z 1091.5), and deapiose-dexylose-derhamnose PD (m/z 813.4). In conclusion, the intestinal first-pass effect such as the presence of efflux functions in the upper ileum, limited but steady intestinal permeability, and gastrointestinal metabolism could explain the low bioavailability and prolonged absorption time of orally administered PD.

Enzymatic activation of double-targeted 5'-O-L-valyl-decitabine prodrug by biphenyl hydrolase-like protein and its molecular design basis.

A primary focus of this research was to explore the activation process and mechanism of decitabine (5-aza-2'-deoxycytidine, DAC) prodrug. Recently, it has been reported that biphenyl hydrolase-like protein (BPHL) can play an important role in the activation of some amino acid nucleoside prodrugs with a general preference for hydrophobic amino acids and 5'-esters. Therefore, we put forward a bold hypothesis that this novel enzyme may be primarily responsible for the activation process of DAC prodrug as well. 5'-O-L-valyl-decitabine (L-val-DAC) was synthesized before and can be transported across biological membranes by the oligopeptide transporter (PEPT1), granting it much greater utility in vivo. In this report, L-val-DAC was found to be a good substrate of BPHL protein (K m 0.59mM; k cat/K m 553.69mM-1s-1). After intestinal absorption, L-val-DAC was rapidly and almost completely hydrolyzed to DAC and L-valine. The catalysis was mainly mediated by the BPHL hydrolase and resulted in the intestinal first-pass effect of L-val-DAC after oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The structural insights using computational molecular docking showed that BPHL had a unique binding mode for L-val-DAC. As a fundamental basis, the simulation was employed to explain the catalytic mechanism in molecular level. In conclusion, BPHL was at least one of the primary candidate enzymes for L-val-DAC prodrug activation. This promising double-targeted prodrug approach have more advantages than the traditional targeted designs due to its higher transport and more predictable activation, thereby leading to a favorable property for oral delivery.

Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects.

PurposeSeveral severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose.MethodsWe conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration.ResultsCompared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30–60) and 18 % (90 % CI 108–129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63–75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study.ConclusionsAlthough it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.

Hepatic, gastric and intestinal first-pass effects of vitexin-2''-O-rhamnoside in rats by ultra-high-performance liquid chromatography.

Previous research in our laboratory found that the absolute bioavailability of vitexin-2''-O-rhamnoside (VR) was quite low at 4.89%. A rapid and sensitive UHPLC method using hesperidin as an internal standard was therefore developed and validated to investigate the reasons for this by determining VR in rat plasma after administering intravenously, intraportally (5 mg/kg), intraduodenally and intragastrically (40 mg/kg) to the rat model of the hepatic, gastric and intestinal first-pass effects. As only a high intestinal first-pass effect of VR was found, that is, there existed a low bioavailability of VR (2.40%), inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A), including verapamil, cyclosporin A and midazolam, and absorption enhancers, including bile salts and borneol, combined with VR, were instilled into duodenum to evaluate the effects on bioavailability of VR. The results demonstrated that area under the concentration-time curve (AUC) values of VR slightly increased after administration of verapamil, cyclosporin A and midazolam, indicating that CYP3A and P-gp do not play an important role in the first-pass effect in the intestine. AUC values of VR significantly increased after administering bile salts or borneol, indicating that the low bioavailability of VR was mainly related to its poor absorption in the intestine.

Abstract 4637: Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients

Abstract Chronic lymphocytic leukemia (CLL) is a B-cell malignancy treated with chemoimmunotherapy. Such treatment results in high response rates but patients may eventually relapse and require alternate therapies. Ibrutinib (PCI-32765), a recently developed novel treatment, is unique in its mechanism as it inhibits Bruton's tyrosine kinase, a key kinase in the B-cell receptor signaling pathway. It's a Biopharmaceutics Classification Systems (BCS) class 2 compound and is metabolized rapidly by CYP3A. Three studies were conducted. The primary objectives were to assess the pharmacokinetics (PK) of ibrutinib under fed and fasted conditions and to assess the impact of food intake timing. Additionally, the safety and tolerability of ibrutinib were assessed. Study 1 was a randomized, open-label, single-center, single-dose, 4-way crossover study in 44 healthy subjects. Study 2 was a multicenter, randomized, repeated-dose crossover study in 16 patients with relapsed or refractory CLL. The ibrutinib dose was 420 mg in both. Study 3 was an open-label, single-center, sequential study to assess absolute bioavailability of ibrutinib 560 mg in 8 healthy subjects. Ibrutinib was well tolerated in these studies. There were no serious adverse events (AEs) or discontinuations due to an AE. There were no clinically significant changes in laboratory safety parameters, electrocardiograms, or vital signs. Administration of ibrutinib to healthy subjects under fasting conditions resulted in approximately 60% of exposure compared to drug intake either 30 min before or 2 h after a high-fat meal. When ibrutinib was taken 30 min after a meal, drug exposure was comparable to the dosing conditions of either 30 min before or 2 h after the meal. Study 2 revealed that under fed conditions, the maximum concentration was 2.24 times greater and the area under the curve was 1.65 times greater compared to the fasted conditions, but similar to uncontrolled food intake conditions. A similar food effect was observed in study 3, in which a standard meal was consumed starting 30 min after dosing. When corrected for repeated dosing in patients, the PK parameters in healthy subjects and patients were comparable. The observed food effect is most likely the result of a decreased (intestinal and hepatic) first-pass effect, rather than an effect on solubilization. Since ibrutinib is a highly permeable compound, residence time in the gut and liver cells could be reduced when mesenteric and portal vein blood flow is increased under fed conditions, making ibrutinib less available to CYP3A clearance. The effect on bioavailability may outweigh the higher clearance due to liver blood flow. In conclusion, food causes no more than a doubling in ibrutinib systemic exposure. Considering the favorable safety profile, ibrutinib can be administered with or without food. Citation Format: Jan de Jong, Juthamas Sukbuntherng, Donna Skee, Joe Murphy, Susan O'Brien, John C. Byrd, Danelle James, Peter Hellemans, Juhui James Jiao, Vijay Chauhan, Italo Poggesi, Erik Mannaert. Evaluation of the pharmacokinetics and food effect of oral ibrutinib in healthy subjects and chronic lymphocytic leukemia patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4637. doi:10.1158/1538-7445.AM2014-4637