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First-pass Intestinal Metabolism of Drugs: Experiences from in vitro, in vivo and simulation studies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (The Biopharmaceutic group)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The bioavailability of a drug can be described as the fraction of an orally administered dose that reaches the systemic circulation and is often limited by first-pass metabolism in the gut and the liver. It is important to have knowledge about these processes since the systemic blood drug concentration is tightly connected to the effect of the drug.

The general aim of this project was to quantitatively examine the role of the intestine in relation to the liver in first-pass metabolism of orally administered drugs. The first-pass metabolism of verapamil and raloxifene was investigated in detail with in vivo, in vitro and simulation studies, using the pig as an experimental model.

The intestine contributed to the same extent as the liver to first-pass metabolism of R/S-verapamil in vivo in pigs. The S-isomer of verapamil was found in lower plasma concentrations compared to the R-isomer after oral dosing. The in vitro metabolism of verapamil in pig and human liver showed interspecies similarity and indicated equal intrinsic clearance for R- and S-verapamil. Through physiologically based pharmacokinetic modeling the stereoselectivity was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut and liver tissue distribution. For raloxifene the intestine was the dominating organ in first-pass glucuronidation in vivo in pigs. Furthermore, the raloxifene concentration entering the intestine or the dose administered in the gut did not influence the plasma PK of raloxifene and indicated that the intestinal metabolism was not saturable with clinical relevant doses. For both verapamil and raloxifene, a time-dependent hepatic metabolism was noted with major consequences to the pharmacokinetic of the drugs.

This project has pointed out the importance of intestinal metabolism in the overall first-pass extraction of drugs and indicates that intestinal metabolism should be considered and evaluated early in drug development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2012. , 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 153
Keyword [en]
pharmacokinetics, metabolism, CYP3A4, CYP2C9, CYP2D6, UGT, glucuronidation, physiologically based pharmacokinetic model, modelling
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
URN: urn:nbn:se:uu:diva-165514ISBN: 978-91-554-8251-0 (print)OAI: oai:DiVA.org:uu-165514DiVA: diva2:474024
Public defence
2012-02-24, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-02-03 Created: 2012-01-09 Last updated: 2012-02-15Bibliographically approved
List of papers
1. Different effects of ketoconazole on the stereoselective first-pass metabolism of R/S-verapamil in the intestine and the liver: important for the mechanistic understanding of first-pass drug-drug interactions
Open this publication in new window or tab >>Different effects of ketoconazole on the stereoselective first-pass metabolism of R/S-verapamil in the intestine and the liver: important for the mechanistic understanding of first-pass drug-drug interactions
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2009 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 11, 2186-2196 p.Article in journal (Refereed) Published
Abstract [en]

In this acute study a pig jejunal intestinal perfusion model with multiple plasma sampling sites and three different administration routes was used to investigate the quantitative contribution of the intestine versus liver to the first-pass extraction of each enantiomer of verapamil (VER). A subclinical dose of ketoconazole (8 mg) was coadministered in the perfusion solution to selectively inhibit gut wall CYP3A. Both enantiomers of VER and its main metabolite norverapamil (NOR) as well as the inhibitor ketoconazole were quantified in all plasma compartments by liquid chromatography-tandem mass spectrometry. The overall first-pass metabolic extraction of VER and the metabolite NOR was shown to be stereoselective with the S-isomer being more extensively extracted. For VER the ratio of R- enantiomer to S-enantiomer was greater in the hepatic vein than in the portal vein (approximately 2.2 versus 1.4), indicating that the stereoselective metabolism of VER in pigs mainly occurs on the first pass through the liver and not in the intestine. Ketoconazole increased the area under the curve from time 0 to 6 h and C(max) of R- and S-VER at least 3-fold in the portal vein, most likely explained by inhibition of gut wall metabolism. Conversely, hepatic extraction was increased because the effect of gut wall metabolism was not observed at the peripheral sampling sites. In conclusion, this study provided novel and more direct information on the contribution of the intestine and the liver, respectively, to the overall first-pass extraction of racemic VER.

Keyword
verapamil, ketoconazole, liver metabolism, intestinal metabolism, pig metabolism, first-pass metabolism
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-110886 (URN)10.1124/dmd.109.028027 (DOI)000270876600010 ()19687151 (PubMedID)
Available from: 2009-11-30 Created: 2009-11-30 Last updated: 2012-05-08Bibliographically approved
2. Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans
Open this publication in new window or tab >>Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans
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2011 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 43, no 3, 89-98 p.Article in journal (Refereed) Published
Abstract [en]

Pigs are becoming increasingly used as a test animal both in pharmacological and toxicological assessment of new drug compounds. For interspecies comparisons and predictions it is important to characterize the expression and function of membrane transport and enzymatic proteins in pigs, particularly at a mechanistic level which will make extrapolation of observation between pig and man to be made with more confidence. The major objective of this report was to increase the integrative knowledge of drug metabolism in pigs and to compare with corresponding data from human liver microsomes. This was done by using human substrates of CYP3A4 (verapamil and testosterone), CYP2C9 (diclofenac) and CYP2D6 (dextromethorphan). In addition, the mRNA expression of important drug metabolizing enzymes and carrier-mediated transporters were assessed in intestine and liver tissues from pigs. It was shown that CYP3A4 activity is quantitatively comparable between the two species but data suggest that qualitative differences may exist. Verapamil showed similar metabolism pattern as in humans and the CYP3A4 inhibitor ketoconazole was able to inhibit the depletion of both R- and S-verapamil. A correlation between individual pig CYP3A mRNA expression and in vivo hepatic extraction ratio was established which indicates that CYP3A is the major determinant factor in both pigs and humans. However, investigations of the metabolism of testosterone resulted in qualitative different metabolite pattern between pigs and humans. The metabolism of diclofenac was very low in pig liver microsomes and did not correlate to corresponding activity in human liver microsomes. In contrast dextromethorphan exhibited a very extensive and rapid metabolism in pig liver microsomes compared to human data. Together with previously determined gene expression data it confirms that CYP2D6 substrates will be very rapidly metabolized in pigs. The mRNA data increased the knowledge of the interindividual variability and the relative expression of different enzymes and transporters in pig intestine and liver. In conclusion, this study has increased the understanding of similarities and differences between pig and human biotransformation of drugs by providing new data for four different model compounds.

Keyword
Verapamil, Testosterone, Pig pharmacokinetics, Dextromethorphan, In vitro metabolism, Pig mRNA expressison
National Category
Pharmaceutical Sciences Cell and Molecular Biology
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-155943 (URN)10.1016/j.ejps.2011.03.008 (DOI)000291906500001 ()
Available from: 2011-07-04 Created: 2011-07-04 Last updated: 2017-12-11Bibliographically approved
3. Binding processes determine the stereoselective intestinal and hepatic extraction of verapamil in vivo
Open this publication in new window or tab >>Binding processes determine the stereoselective intestinal and hepatic extraction of verapamil in vivo
2012 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 11, 3034-3045 p.Article in journal (Other academic) Published
Abstract [en]

The aim of this study was to investigate the mechanisms that might explain the observed route-dependent stereoselective pharmacokinetics (PK) of R/S-verapamil (R/S-VER) following oral and intravenous (iv) administration, by using a novel pig-specific physiologically based pharmacokinetic (PBPK) model suitable for investigations of first-pass extraction in the gut (EG) and the liver (EH). The PBPK model consisted of eight tissue compartments and was designed to simultaneously model the plasma concentration–time (PCT) profiles from three sampling sites after intrajejunal (ij) or iv administration of VER. The PBPK model successfully described the observed PCT profiles and EH over time for R- and S-VER. Extensive tissue binding to gut mucosa, liver, and lungs was an important determinant of the observed PK data. The stereoselective PK of VER was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut mucosa and liver tissue distribution. The absence of stereoselectivity after iv dosing indicates that the first-pass tissue binding effect is an important factor in determining the steroselective PK of R/S-VER after oral administration. Additionally a combination of extensive liver tissue binding and a metabolite inhibition mechanism explained the time-dependent EH for both R- and S-VER. An in vitroin vivocorrelation of absorption needs to consider these processes because tissue binding may confound analysis of a drug’s biopharmaceutical properties when using classical deconvolution or convolution techniques. In conclusion, a combination of PK data from multiple plasma sampling sites and a PBPK modeling approach provided a mechanistic understanding of processes involved in the intestinal absorption and first-pass extraction ofR- and S-VER.

Keyword
verapamil, PBPK, hepatic extraction, gut wall extraction, first-pass metabolism
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-165509 (URN)10.1021/mp3000875 (DOI)000313769200008 ()
Available from: 2012-01-09 Created: 2012-01-09 Last updated: 2017-12-08Bibliographically approved
4. Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery
Open this publication in new window or tab >>Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery
2012 (English)In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 42, no 9, 917-928 p.Article in journal (Refereed) Published
Abstract [en]

1. 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'-beta-glucuronide (R-4-G).

2. 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 similar to 50% and as in humans the bioavailability become low (similar to 7%) in pigs. Interestingly the E-H of raloxifene and R-4-G was time-dependent after i.j. administration.

3. 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.

Keyword
Raloxifene, glucuronidation, pigs, intestinal metabolism, first-pass metabolism
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-165511 (URN)10.3109/00498254.2012.683497 (DOI)000307301900011 ()
Available from: 2012-01-09 Created: 2012-01-09 Last updated: 2017-12-08Bibliographically approved

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