Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique

Richter, Oliver von; Greiner, Bernd; Fromm, Martin F.; Fraser, Robert; Omari, Taher; Barclay, Murray L.; Dent, John G.; Somogyi, Andrew A.; Eichelbaum, Michel

doi:10.1067/mcp.2001.117937

Cited by 83 publications

(89 citation statements)

References 25 publications

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“…This was indeed one of the main limitations to use of ERMBT in the current study, although our results were similar in subjects carrying the CC genotype compared with those who did not (i.e. carrying the TT genotype).Although the total mass of CYP3A4 in the entire small intestine has been estimated to be around 1% of that in the liver, there is increasing evidence that intestinal CYP3A can contribute significantly, in some cases equally to hepatic CYP3A, to the overall first-pass metabolism of several drugs [43][44][45][46]. In addition, rifampicin has been shown to be capable of inducing intestinal CYP3A4 [47].…”

contrasting

confidence: 40%

“…Although the total mass of CYP3A4 in the entire small intestine has been estimated to be around 1% of that in the liver, there is increasing evidence that intestinal CYP3A can contribute significantly, in some cases equally to hepatic CYP3A, to the overall first-pass metabolism of several drugs [43][44][45][46]. In addition, rifampicin has been shown to be capable of inducing intestinal CYP3A4 [47].…”

Section: Control Phasementioning

confidence: 99%

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Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

Chhun

Verstuyft

Rizzo-Padoin

et al. 2009

Brit J Clinical Pharma

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AIMSWe aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P-glycoprotein (P-gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P-gp substrate. METHODSAn open-label, randomized, two-phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by their ABCB1 C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg -1 daily). Gefitinib plasma concentrations were determined by high-performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the 14 C-erythromycin breath test (ERMBT) and the ABCB1 and CYP2D6 genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively. RESULTSFollowing treatment with phenytoin, mean gefitinib Cmax and AUC0-• decreased by 26 Ϯ 44% [95% confidence interval (CI) for the difference 5-48%, P = 0.005] and 47 Ϯ 26% (95% CI for the difference 34-60%, P = 0.001), respectively, and apparent oral clearance increased by 126 Ϯ 93% (95% CI for the difference 80-172%, P = 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 Ϯ 44% (95% CI 75-105%, P < 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent of ABCB1 genetic polymorphism. The CYP2D6 genotype was slightly but significantly related to gefitinib clearance (P = 0.04) during the control phase. CONCLUSIONSThe significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent of ABCB1 polymorphism, but may involve presystemic CYP3A-mediated intestinal first-pass.British Journal of Clinical Pharmacology DOI:10.1111DOI:10. /j.1365DOI:10. -2125DOI:10. .2009 226 / Br J Clin Pharmacol / 68:2 / 226-237 IntroductionGefitinib (ZD 1839) is the first available oral quinazoline compound referred to as a 'selective' epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor [1]. It provides an antiproliferative effect by blocking signal transduction from the EGF receptor and has been recently approved as third-line monotherapy in Japan for the treatment of cancer patients who present with locally advanced inoperable or recurrent non-small cell lung carcinoma. Gefitinib systemic exposure is rather complex and highly variable between subjects [1]. Gefitinib is a high-extraction drug with a mean volume of distribution of about 1500 l in humans and is subject to complex and extensive presystemic first-pass [1]. Drug-transport proteins including P-glycoprotein (P-gp) and drug-metabolizing enzymes, e.g. cytochromes P450 (CYP), are relevant factors affecting the pharmacokinetic profile of gefitinib. Preclinical studies performed with human liver microsomes suggested that CYP3A4 was the major enzyme involved in gefitinib metabolism.The 3A4 isoform accounts for as much as 35% of total CYPs expressed in the liver and...

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contrasting

confidence: 40%

Section: Control Phasementioning

confidence: 99%

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

Chhun

Verstuyft

Rizzo-Padoin

et al. 2009

Brit J Clinical Pharma

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“…administration of VP (80 mg/kg) to healthy volunteers (Hashiguchi et al, 1996), corrected for the B/P ratio (Robinson and Mehvar, 1996), were 29 and 121 ng ⅐ h/ml, respectively, and the corresponding AUCs of the NVP enantiomers were 80 and 168 ng ⅐ h/ml. First-pass metabolism of VP in enterocytes has also been reported in humans (Sandström et al, 1999;von Richter et al, 2001). The extraction ratios of R-and S-VP by enterocytes were 0.49 and 0.68, respectively, and those by liver were 0.63 and 0.79, respectively (Sandström et al, 1999).…”

Section: Stereoselective First-pass Metabolism Of Verapamilmentioning

confidence: 88%

Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats

Hanada¹,

Ikemi²,

Kukita³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Verapamil (VP) is used as a racemate but shows stereoselective pharmacokinetics and pharmacodynamics. It undergoes extensive first-pass metabolism. Stereoselective first-pass metabolism in the intestine and liver was investigated in vivo and in vitro to determine its impact on the disposition of VP and its main metabolite, norverapamil (NVP). VP racemate was administered to rats i.v., p.o., and via the portal vein. The formation rates of the main metabolites of the VP enantiomers were estimated in an in vitro intestinal microsomal study. The hepatic bioavailability of VP showed saturable metabolism, and the hepatic bioavailability of R-VP was higher than that of S-VP. Conversely, the intestinal bioavailability of R-VP was lower than that of S-VP, resulting in a higher systemic bioavailability of S-VP. The pharmacokinetics of the NVP enantiomers was similar. These results suggest that the stereoselectivity of the total bioavailability of VP is determined by first-pass metabolism in the small intestine and liver, and that the NVP enantiomers observed in the systemic circulation after p.o. administration of VP racemate originate mainly from the liver in rats.The first-pass metabolism of drugs in the small intestine and liver limits their bioavailability to the systemic circulation. Although the effects of first-pass metabolism in the liver after p.o. administration have been well studied, it is now known that many drugs also undergo first-pass metabolism in the small intestine. Reductions in the firstpass metabolism of these drugs, caused by drug-drug interactions or disease states, may occur to a different extent in the small intestine and liver. Therefore, it is very important to elucidate the mechanisms underlying first-pass metabolism, as well as the separate contributions of metabolism in the small intestine and liver, to be able to predict changes in oral bioavailability.Verapamil (VP) is a calcium antagonist used clinically for the treatment of hypertension and for prophylaxis of supraventricular and ventricular arrhythmias. VP has a relatively narrow therapeutic plasma concentration range and shows relatively large interindividual variations in its pharmacokinetics and pharmacodynamics (Vogelgesang et al., 1984;Echizen et al., 1985a Echizen et al., ,b, 1988. Although VP is commercially available as a racemic mixture, its pharmacological effects and disposition have been reported to show stereoselectivity in both humans and animals. The antiarrhythmic effect of S-VP, as estimated by electrocardiograph, is 10 to 20 times higher than that of R-VP in humans (Echizen et al., 1985a,b). The oral bioavailability of S-VP is approximately 20% in humans, whereas that of R-VP is approximately 50% (Vogelgesang et al., 1984;Echizen et al., 1985a Echizen et al., ,b, 1988. The plasma protein binding of R-VP is higher than that of S-VP (free fractions: 7 and 12%, respectively) (Gross et al., 1988;Robinson and Mehvar, 1996). We have previously reported that VP binds enantioselectively to ␣1-acid glycoprotein and ...

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“…Although basic knowledge concerning human intestinal drug enzyme and transporter expression has been collected over the past decade (Obach et al, 2001;Thorn et al, 2005), the ultimate proof for their significance has been given by in vivo studies. For several compounds, such as cyclosporin, verapamil, and midazolam, in vivo studies have shown significant first-pass metabolism by the intestinal wall (Kolars et al, 1991;von Richter et al, 2001;Glaeser et al, 2004). The significance of the intestine in determining the faith of drugs within the body is not only expressed by its high capacity to metabolize drugs but also by its sensitivity to induction and inhibition of drug-metabolizing enzymes (Pelkonen et al, 2001), in addition to the interplay between transporters and metabolic activity (Suzuki and Sugiyama, 2000;Benet et al, 2004;Jeong et al, 2005).…”

mentioning

confidence: 99%

“…Although the liver has long been thought to play the major role in drug metabolism, the metabolic capacity of the intestine has been increasingly recognized (von Richter et al, 2001;Glaeser et al, 2004).…”

mentioning

confidence: 99%

Innovative Methods to Study Human Intestinal Drug Metabolism in Vitro: Precision-Cut Slices Compared with Ussing Chamber Preparations

Kerkhof¹,

Ungell²,

Sjöberg³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Predictive in vitro methods to investigate drug metabolism in the human intestine using intact tissue are of high importance. Therefore, we studied the metabolic activity of human small intestinal and colon slices and compared it with the metabolic activity of the same human intestinal segments using the Ussing chamber technique. The metabolic activity was evaluated using substrates to both phase I and phase II reactions: testosterone, 7-hydroxycoumarin (7HC), and a mixture of cytochrome P450 (P450) substrates (midazolam, diclofenac, coumarin, and bufuralol). In slices of human proximal jejunum, the metabolic activity of several P450-mediated and conjugation reactions remained constant up to 4 h of incubation. In the colon slices, conjugation rates were virtually equal to those in small intestine, whereas P450-mediated conversions occurred much slower. In both organs, morphological evaluation and ATP content implied tissue integrity within this period. P450 conversions using the Ussing chamber technique showed that the metabolic rate (sum of metabolites measured in apical, basolateral, and tissue compartments) was constant up to 3 h. For 7HC conjugations, the metabolic rate remained constant up to 4 h. The distribution of the metabolites in the compartments differed between the substrates. Overall, metabolic rates were surprisingly similar in both techniques and appear similar to or even higher than in liver. In conclusion, this study shows that both human intestinal precision-cut slices and Ussing chamber preparations provide useful tools for in vitro biotransformation studies.

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Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique

Abstract: First-pass metabolism by the intestinal wall is extensive and contributes to the same extent as the liver to low bioavailability of some drugs such as verapamil. Moreover, intestinal secretion is as important as biliary excretion for the elimination of metabolites.

Cited by 83 publications

References 25 publications

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats

Innovative Methods to Study Human Intestinal Drug Metabolism in Vitro: Precision-Cut Slices Compared with Ussing Chamber Preparations

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Determination of in vivo absorption, metabolism, and transport of drugs by the human intestinal wall and liver with a novel perfusion technique

Abstract: First-pass metabolism by the intestinal wall is extensive and contributes to the same extent as the liver to low bioavailability of some drugs such as verapamil. Moreover, intestinal secretion is as important as biliary excretion for the elimination of metabolites.

Cited by 83 publications

References 25 publications

Gefitinib–phenytoin interaction is not correlated with the 14C‐erythromycin breath test in healthy male volunteers

Gefitinib–phenytoin interaction is not correlated with the 14C‐erythromycin breath test in healthy male volunteers

Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats

Innovative Methods to Study Human Intestinal Drug Metabolism in Vitro: Precision-Cut Slices Compared with Ussing Chamber Preparations

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Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers

Gefitinib–phenytoin interaction is not correlated with the ¹⁴C‐erythromycin breath test in healthy male volunteers