Impact of Intestinal Glucuronidation on the Pharmacokinetics of Raloxifene

Kosaka, Keigo; Sakai, Norifumi; Endo, Yuya; Fukuhara, Yuga; Tsuda-Tsukimoto, Minoru; Ohtsuka, Tatsuyuki; Kino, Ichiro; Tanimoto, Tomohiko; Takeba, Naomi; Takahashi, Masakatsu; Kume, Toshiyuki

doi:10.1124/dmd.111.040030

Cited by 32 publications

(19 citation statements)

References 36 publications

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“…The F a ⅐ F g of famotidine was 0.19, because it appears to be absorbed predominantly via the paracellular pathway (Lee and Thakker, 1999). Previous reports showed that F a ⅐ F g of raloxifene in Gunn rats deficient in UDP-glucuronosyltransferase 1A and wild-type Wistar rats was 0.63 and 0.34, respectively (Kosaka et al, 2011), suggesting that the low F a ⅐ F g of raloxifene was due to glucuronidation and low absorption in the intestine. Taken together, the results of this study of intestinal and hepatic availability in cannulated rats were in agreement with these previous reports.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

et al. 2012

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ABSTRACT:To understand the rate-limiting process of oral drug absorption, not only total bioavailability (F) but also intestinal (F a ⅐ F g ) and hepatic (F h ) availability after oral administration should be evaluated. Usually, F a ⅐ F g of drug is calculated from pharmacokinetic parameters after intravenous and oral administration. This approach is influenced markedly by the estimated value of F h , which varies with the hepatic blood flow used in the calculations. In this study, portal vein-cannulated rats were used to calculate the F a ⅐ F g of drugs from a single oral dosing experiment without data from intravenous injection. Portal vein-cannulated rats were prepared by a new operative method that enables stable portal vein blood flow. This surgery had no effects on hepatic blood flow and metabolic activity. Our method for calculating F a ⅐ F g was validated by determining both portal and systemic plasma concentration profiles of various drugs possessing different pharmacokinetic properties after oral administration to the portal vein-cannulated rats. Simulation of portal and systemic plasma concentrations by physiologically based pharmacokinetic modeling indicated that the balance of the absorption rate constant (k a ) and elimination rate constant (k e ) resulted in different patterns in portal and systemic plasma concentration-time profiles. This study is expected to provide a new experimental animal model that enables identification of the factors that limit oral bioavailability and to provide pharmacokinetic information on the oral absorption process of drugs during drug discovery.

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Section: Discussionmentioning

confidence: 99%

“…F a ⅐ F g is evaluated by measuring the difference between portal and systemic blood concentrations after oral dosing (Kosaka et al, 2011;Furukawa et al, 2012). Thus, this method enables the estimation of F a ⅐ F g in individual animals without intravenous drug administration.…”

Section: Introductionmentioning

confidence: 99%

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

et al. 2012

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“…However, considering an efflux ratio of 1.5 it is not likely that the transport will affect the extent of absorption in vivo (Jeong et al, 2004). Further on, excretion of raloxifene glucuronide and sulphate metabolites has been reported to be mediated by MRP and/or organic anion transporter but not P-gp (Jeong et al, 2004, Kosaka et al, 2011.…”

Section: Research Articlementioning

confidence: 95%

“…Also from clinical data, based on peripheral plasma concentration, the intestine is assumed to be the major organ involved in the first-pass metabolism of raloxifene (Mizuma, 2009). In vivo in rats, raloxifene was suggested to be glucuronidated in both the intestine and liver since the product of fraction absorbed and intestinal availability and hepatic availability were two-fold higher in Gunn rats (UGT1Adeficient rats) compared to Wistar rats (Kosaka et al, 2011). Based on the Caco-2-cell culture model raloxifene was shown to be a substrate to both multidrug resistance protein (MRP) and P-glycoprotein (P-gp).…”

Section: Research Articlementioning

confidence: 98%

Extensive intestinal glucuronidation of raloxifenein vivoin pigs and impact for oral drug delivery

Thörn¹,

Yasin²,

Dickinson³

et al. 2012

Xenobiotica

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In this study an advanced multisampling site pig model, with simultaneous venous blood sampling pre- and post liver, was applied to quantify the role of the intestine in relation to the liver in first-pass glucuronidation of raloxifene in vivo. The pharmacokinetic of raloxifene (a BCS/BDDCS class II compound) in humans is characterized by extensive metabolism (>90%) and the major metabolite is the 4'-β-glucuronide (R-4-G). Following intra-jejunal (i.j.) single dose administration in pigs raloxifene was metabolized in the gut (E(G)) during first-pass to more than 70% and a high concentration (AUC(0-6 h) ratio R-4-G/raloxifene >100) of R-4-G was reached in the portal vein. The hepatic extraction (E(H)) of raloxifene was ~50% and as in humans the bioavailability become low (~7%) in pigs. Interestingly the E(H) of raloxifene and R-4-G was time-dependent after i.j. administration. It is clear that the gut was the dominating organ in first-pass extraction of raloxifene in vivo in pigs. The quantification in this study support earlier human data and emphasize that intestinal glucuronidation should be considered early in the pharmaceutical development.

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“…The tubes containing microsomes were gently shaken for 10 s and then allowed to stand for 15 min on ice. Fractions were then centrifuged at 25,000 × g for 10 min 152 . Pellets were resuspended in 0.25 M sucrose/0.02 M Tris buffer.…”

Section: Preparation Of Rat Intestinal Microsomesmentioning

confidence: 99%

The Comparison of Rat and Human Intestinal and Hepatic Glucuronidation of Enterolactone Derived from Flaxseed Lignans

Lin¹,

Krol²,

Alcorn

2013

NPJ

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The mammalian lignan, enterolactone (EL), is a gut microbe metabolite of plant lignan secoisolariciresinol diglucoside (SDG), which is most abundant in flaxseed. Numerous epidemiological, experimental and clinical studies suggest the protective effects of EL against various chronic diseases such as cancer, cardiovascular disease, and inflammation. However, EL's oral bioavailability is low and highly variable due to extensive first-pass metabolism, especially glucuronidation, which results in the large amount of glucuronide metabolites but low levels of free EL in human plasma. Hepatocytes and enterocytes express UDP-glucuronosyltransferases (UGT), the enzymes responsible for the conjugation of glucuronic acid to EL. To better understand the contribution of liver and intestine to the first-pass glucuronidation, I conducted an in vitro enzyme kinetic analysis of EL glucuronidation using hepatic and intestinal microsomal fractions from both human and rat.An intrinsic clearance (CL int ) value was calculated using the substrate depletion approach. In addition to monitoring substrate depletion, high-pressure liquid chromatography (HPLC) analysis allowed detection of EL glucuronides, which were further substantiated by LC-MS.EL monoglucuronide was identified in rat and human intestinal and liver microsomes.Enzyme kinetic studies indicated the extent of hepatic microsomal glucuronidation exceeded intestinal glucuronidation in both human and rat, while the human liver CL int value was slightly higher than that of rat liver. The CL int value generated in human intestinal microsomes was only one third of the value of human liver, whereas, the CL int of rat jejunum or colon was one-twentieth of rat liver, suggesting the human intestine makes a greater contribution to EL glucuronidation than rat intestine. These results suggest that both liver and intestine contribute to EL glucuronidation and the human intestine may exert a greater influence on the first-pass glucuronidation of EL than rat intestine, thereby significantly decreasing EL's oral bioavailability. The rat might underestimate the extent of intestinal metabolism of EL relative to human.iii

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Impact of Intestinal Glucuronidation on the Pharmacokinetics of Raloxifene

Cited by 32 publications

References 36 publications

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

Assessment of Intestinal Availability of Various Drugs in the Oral Absorption Process Using Portal Vein-Cannulated Rats

Extensive intestinal glucuronidation of raloxifenein vivoin pigs and impact for oral drug delivery

The Comparison of Rat and Human Intestinal and Hepatic Glucuronidation of Enterolactone Derived from Flaxseed Lignans

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