Contribution of Carboxylesterase in Hamster to the Intestinal First-Pass Loss and Low Bioavailability of Ethyl Piperate, an Effective Lipid-Lowering Drug Candidate
Youli LuNarisu BaoGereltu BorjihanYanling MaMiaomiao HuChen YuShuijun LiJingying JiaYang DingYiping Wang
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Ethyl piperate is an effective lipid-lowering drug candidate synthesized from piperine. However, its pharmacokinetic characteristics and oral absorption process remain unclear. A liquid chromatography-tandem mass spectrometry method was applied to determine the oral bioavailability of ethyl piperate. Simulated gastrointestinal pH conditions and intestinal washings were prepared to investigate their contributions to the loss of ethyl piperate. Hydrolysis by carboxylesterase (CES) was evaluated in vitro using microsomes and S9 fractions. In situ intestinal single-pass perfusion experiments were performed to estimate the role of CES in ethyl piperate absorption. The bioavailability of ethyl piperate was extremely low (0.47%) in hamster independent of gastrointestinal environmental effects. Ethyl piperate was a typical substrate of CES with kinetic parameters Km and Vmax of 7.56 ± 1.491 μM and 0.16 ± 0.008 nmol · min−1 · mg protein−1, respectively. CES was responsible for 85.8% of the intestinal hydrolysis of ethyl piperate. Specific inhibition of CES with bis-p-nitrophenyl phosphate (BNPP), decreased degradation clearance to 36% of control with no significant change in absorption clearance. This contrasted with the results of Caco-2 monolayer experiments, which showed a dramatic increase in the apparent permeability coefficient after BNPP treatment. mRNA levels for the CES isozyme, CES2A3, were similar among the three regions of hamster intestine and 60% less than those in liver; CES1B1 mRNA levels were even lower in the intestine and showed a proximal-to-distal decrease. In conclusion, CES markedly contributes to intestinal first-pass hydrolysis of ethyl piperate that is sufficient, but not necessary, to cause the observed extremely low bioavailability.Keywords:
Carboxylesterase
CYP3A
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Caco-2
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Plasma levels
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The pharmacokinetics of senkyunolide A, one of the major bioactive ingredients in the traditional Chinese medicinal herb Rhizoma Chuanxiong, which is commonly used for the treatment of cardiovascular diseases, was studied in rats. After intravenous (IV) administration, senkyunolide A was extensively distributed (Vd/F: 6.74 ± 0.73 L/kg) and rapidly eliminated from the plasma (CL/F: 7.20 ± 0.48 L/h per kilogram and t1/2: 0.65 ± 0.06 hr). Hepatic metabolism was suggested as the major route of senkyunolide A elimination as indicated by the results of in vitro S9 fraction study. After intraperitoneal (IP) administration, senkyunolide A exhibited dose-independent pharmacokinetics. The absorption after IP administration was rapid (Tmax: 0.04 ± 0.01 hours), and the bioavailability was 75%. After oral administration, senkyunolide A was also absorbed rapidly (Tmax: 0.21 ± 0.08 hours); however, its oral bioavailability was low (∼8%). The contributing factors were determined to be instability in the gastrointestinal tract (accounting for 67% of the loss) and hepatic first-pass metabolism (accounting for another 25%). Pharmacokinetics of senkyunolide A were unaltered when Chuanxiong extract was administered, which suggests that components in the extract have insignificant effects on senkyunolide A pharmacokinetics.
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Atenolol
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The pharmacokinetics of pafenolol, a highly selective beta 1-adrenoceptor antagonist, have been studied in starved and unstarved rats. Separate groups received intravenous doses (0.3 and 3.0 mumol kg-1) and oral doses (1 and 25 mumol kg-1). The systemic clearance of pafenolol was constant in the dose range investigated where the absolute oral bioavailability increased from 15 to 27 per cent in the starved and from 9.1 to 21 per cent in the unstarved rats, when the oral dose was raised from 1 to 25 mumol kg-1. The blood concentration profile after an oral solution of pafenolol exhibited two peaks in the majority of the rats. The major part of the absorption was associated with the second peak which appeared about 4 h after dosing in both starved and unstarved rats. Food lowered the degree of bioavailability and shifted the tmax1 to about 1 hour compared to half an hour in starved rats. The low bioavailability was primarily due to incomplete uptake from the gastrointestinal tract. Our study shows that pafenolol is absorbed in a similar way to that in man. The mechanisms behind the dose-dependent bioavailability and the two peaks in the absorption profile after an oral solution will be further explained in the rat.
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In order to characterize the pharmacokinetics, bioavailability and tissue distribution of geniposide following intravenous and peroral administration to rats, a reliable gradient HPLC-based method has been developed and validated. After p.o. administration of geniposide, the peak concentration of geniposide in plasma occurred at 1 h and plasma geniposide was eliminated nearly completely within 12 h. The AUC(0→∞) values of geniposide were 6.99 ± 1.27 h · µg/ml and 6.76 ± 1.23 h · µg/ml after i.v. administration of 10 mg/kg and p.o. administration of 100 mg/kg of geniposide, respectively. The absolute oral bioavailability (%F) of geniposide was calculated as 9.67%. After p.o. administration of geniposide, the AUC(0→4h) values in tissues were in the order of kidney > spleen > liver > heart > lung > brain. This study improved the understanding of the pharmacokinetics, bioavailability and tissue distribution of geniposide in rats and may provide a meaningful basis for clinical application of such a bioactive compound of herbal medicines.
Tissue distribution
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Abstract A new once‐daily formulation of raltegravir, an integrase strand transfer inhibitor indicated in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus–1 infection, is under development. Single‐dose and steady‐state pharmacokinetics of 1200 mg for 2 formulations of raltegravir were characterized in 2 open‐label phase 1 studies in healthy male and female subjects aged 18 to 55 years. The new raltegravir 600‐mg formulation had a higher relative bioavailability compared with the 400‐mg tablets. Once absorbed, both 3 × 400‐mg and 2 × 600‐mg dosage forms of raltegravir exhibited similar systemic pharmacokinetics; in dictating bioavailability, differences were from increased absorption that was the result of improved in vivo disintegration/dissolution. Food had a smaller effect on the pharmacokinetics of raltegravir when given as 2 × 600‐mg formulation (42% vs 73% decrease in AUC 0–last ). Steady state was generally reached in 2 days, with little to no accumulation with multiple‐dose administration. Raltegravir 1200 mg was found to exhibit pharmacokinetic properties amenable for once‐daily dosing and was generally well tolerated in healthy subjects after single and multiple doses. The new formulation improved the bioavailability of this Biopharmaceutics Classification System class II compound.
Raltegravir
Biopharmaceutics
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OBJECTIVE To determine pharmacokinetic and relative bioavailability of diclofence sodium sustained release micropellets(DS?SRMP) in vivo.METHODS UV method was established for assaying serum diclofence sodium concentrations in rabbits. To study theabsorptive kinetics and bioavailability of DS?SRMP. RESULTS The absorption rate of DS?SRMP in vivo was found to conform apparent zero orderkinetics(Ka 0= 12.14% /h)during the first 8 h .CONCLUSIONS The studies of pharmacokinetics in vivo indicated DS SRMP had sustained release effect.The drug concentration in blood was steady after oral administration, it could last longer and reduce the times of adminstration. The preparation release stability, bioavailability and safty.
Diclofenac Sodium
Absorption rate
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