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Lin, Deming; Wang, H. S.; Lin, Man-Zhen; Lin, Michael; Wu, Yifeng

doi:10.1023/a:1010199004211

Cited by 17 publications

(5 citation statements)

References 4 publications

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“…The mem-*Address correspondence to this author at the Department of Pharmacokinetics & Drug Delivery, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands; Tel: +31 50 363 3272; Fax: +31 50 363 3247; E-mail: g.m.m.groothuis@rug.nl bers of the cytochrome P450 (CYP) superfamily are the principle enzymes involved in the biotransformation of drugs [15]. The amounts of CYPs in the intestine show a large inter-individual variation as has been described for CYP1A1 activity [16] and CYP3A protein [17] differing over 15-fold between individuals.…”

Section: Introductionmentioning

confidence: 99%

“…The significance of intestinal phase II metabolism to total drug metabolism has not been extensively described, but was shown to be significant for sulphation of terbutaline and isoproterenol [15]. For the glucuronidation of morphine in the rat was shown to contribute for more than 50% of orally dosed morphine [33].…”

Section: Introductionmentioning

confidence: 99%

“…The residence time of these drugs within the intestinal cells is thereby prolonged and the opportunity for drug metabolism is increased. According to Lin et al [15], the Km values of Pgp are relatively low, indicating that they are readily saturated when drugs are administered at high doses, therefore the contribution of Pgp can only be relevant for drugs with low solubility or low permeability, or for drugs that dosed in low concentrations. Oral administration of digoxin to volunteers with silent polymorphism in exon 26 (G 3435T) of MDR1 results in significantly higher digoxin plasma levels and AUC in comparison with healthy (non-polymorphistic) volunteers which provides direct evidence for a role of intestinal MDR1 in determining the oral bioavailability [42].…”

Section: Introductionmentioning

confidence: 99%

“…It is suggested that intestinal enzymes respond to a greater extent than hepatic enzymes to orally administered inducers because of more direct exposure to higher concentrations of the inducers [15].…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Methods to Study Intestinal Drug Metabolism

Kerkhof¹,

Graaf²,

Groothuis

2007

CDM

109

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Although the liver has long been thought to play the major role in drug metabolism, also the metabolic capacity of the intestine is more and more recognized. In vivo studies eventually pointed out not only the significance of first-pass metabolism by the intestinal wall for the bioavailability of several compounds, but also the relevance of transporters in this process. Only a few methods are available to study drug metabolism in vivo or in situ and with most of these methods it remains difficult to discriminate between the contribution of liver and extrahepatic tissues. To study intestinal drug metabolism in vitro, apart from subcellular fractions, several intact cell systems are nowadays available. This review discusses the available intestinal in vitro methods to study drug metabolism. The advantages and limitations of intact cell systems (isolated intestinal perfusion, everted sac, Ussing chamber preparations, biopsies, precision-cut slices, primary cells), subcellular fractions (S9 fractions, microsomes) and intestinal cell lines (caco-2, LS180 cells amongst others) are discussed. Their applicability to different species and to study phase I and II metabolism/transport and drug-drug interactions are summarized. Furthermore, causes of variation within and between methods are discussed and metabolic rates obtained with different methods are compared. Whereas subcellular fractions and cell lines are efficient methods to study mechanistic aspects of drug metabolism at the enzyme level, the isolated intestinal perfusion, everted sac and Ussing chamber appear particularly useful for studying drug metabolism of rapidly metabolised drugs and interactions with transporters. Biopsies, precision-cut slices and primary cells seem all appropriate to study induction and metabolism of slowly metabolised drugs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In Vitro Methods to Study Intestinal Drug Metabolism

Kerkhof¹,

Graaf²,

Groothuis

2007

CDM

109

View full text Add to dashboard Cite

show abstract

“…One recent comprehensive d iscussion is to be found in Musan (1995), who builds on the work of Enç (1981) 1997a, 1997b), in some provocative work, has also employed and defended stages in the a nalysis of St'at'imcets (Lillooet Salish) noun phrases in order to account for their temporal restrictedness. Lin (1999) has proposed that stages be countenanced in order to account for the semantics of shenme 'what' in donkey-type conditional sentences in Chinese (also exa mined in great detail by Huang and Cheng (1996) though they focus on the semantics of 'w ho', which turns out to have some different properties). The stage/individual contrast has al so been invoked in unpublished work to form an account of the semantic distinction betwee n the Japanese anaphoric expressions sore vs. kare.…”

Section: A Codicil On Stagesmentioning

confidence: 99%