Intestinal metabolism first-pass

Matsumoto S, Hirama T, Matsubara T, Nagata K, Yamazoe Y. 2002. Involvement of CYP2J2 on the intestinal first-pass metabolism of antihistamine drug, astemizole. Drug Metab... 

Andersen V, Pedersen N, Larsen NE, Sonne J, Larsen S. Intestinal first pass metabolism of midazolam in liver cirrhosis—effect of grapefruit juiee. Br J Clin Pharmacol 2002 54(2) 120-124. 

Route of Administration and Intestinal First-Pass Metabolism... 

Although we have assumed that there is no mucosal diffusional barrier for the CYP3A substrate, the unbound inhibitor concentration in the intestinal epithelia (7gm) may or may not be equivalent to that in plasma and the liver (7U). 7gm may exceed the unbound portal plasma concentration during the inhibitor absorption phase or be less than the unbound portal concentration postabsorption if there is not rapid equilibrium between the intracellular and portal plasma compartments (i.e., a basolateral membrane diffusional barrier exists). This obviously makes it challenging to anticipate the quantitative effect of an inhibitor on intestinal first-pass metabolism. 

One final consideration of drug interactions involving intestinal CYP3A is the fact that differential modulation of intestinal and hepatic CYP3A is possible. Simultaneous inhibition of intestinal first-pass metabolism and stimulation or induction of hepatic first-pass metabolism has been reported for the interaction between the herbal supplement echinacea (Echinacea purpurea root) and... 

The extent to which P-gp activity influences intestinal CYP3A-mediated first-pass extraction in vivo is still unclear. However, Johnson et al. (148) did show that selective inhibition of P-gp mediated verapamil efflux with PSC833 reduced the extent of intestinal first-pass metabolism in an autoperfused rat... 

Lin JH, Chiba M, Chen IW, et al. Effect of dexamethasone on the intestinal first-pass metabolism of indinavir in rats evidence of cytochrome P-450 3A and P-glycoprotein induction. Drug Metab Dispos 1999 27 1187-1193. 

Yang, J., Jamei, M., Rowland Yeo, K., Tucker, G.T. and Rostami-Hodjegan, A. (2007) Prediction of intestinal first-pass metabolism. Current Drug Metabolism, 8, 676-684. 

Kato, M., Chiba, K., Hisaka, A., Ishigami, M., Kayama, M., Mizuno, N., Nagata, Y., Takaluwa, S. et al. (2003) The intestinal first-pass metabolism of substrates... 

Zhang, L., Lin, G. and Zuo, Z. (2007) Involvement of UDP-glucuronosyltransferases in the extensive liver and intestinal first-pass metabolism of flavonoid baicalein. Pharmaceutical Research, 24, 81-89. 

Kato, M., Intestinal first-pass metabolism of CYP3A4 substrates. Drug Metab. Pharmaco., 23(2), 87, 2008. 

Nishimura, T. et al., Asymmetric intestinal first-pass metabolism causes minimal oral bioavailability of midazolam in cynomolgus monkey, Drug Metab. Dispos., 35(8), 1275, 2007. 

CYP2J subfamily. CYP2J2 is the only gene of this subfamily. It is known to be expressed in many extrahepatic tissues and may play a role in the oxidative bioactivation of arachidonic acid to form epoxyeicosatrienoic acids, which modulate bronchial smooth muscle tone and airway transepithelial ion transport [53], CYP2J2 is also active toward other compounds such as linoleic acid and testosterone. Recently, it has been reported that CYP2J2 is involved in the intestinal first-pass metabolism of an antihistamine drug, astemizole [54],... 

Although hepatic metabolism continues to be the most important route of metabolism tor xenobiotics, the ability of the liver and intestine to metabolize substances to either pharmacologically inactive or bioactive metabolites before reaching systemic blood levels is called prehepatic or presystemic first pass metabolism, which results in the low systemic availability tor susceptible drugs. Sulfation and glucuronidation are major pathways of presystemic intestinal first-pass metabolism in humans tor acetaminophen, phenylephrine, terbutaline, albuterol, tenoterol, and isoproterenol. 

Following oral administration, norethindrone acetate is completely and rapidly deacetylated by hepatic and intestinal first-pass metabolism to norethindrone, with an oral bioavailability of approximately 64%. Subsequent metabolism of norethindrone includes reduction of the double bond to both the 5a- and 5p-dihydronorethindrone products as well as reduction of the ketone. The pharmacokinetics for norethindrone acetate are indistinguishable from that of orally administered norethindrone. Roughly 36% of norethindrone is bound to SHBG, and 61% is bound to albumin (11). 

Galetin A, Gertz M, Houston JB. Potential role of intestinal first-pass metabolism in the prediction of drug-drug interactions. Expert Opin Drug Metab Toxicol 2008 4 909-922. 

Kato M, Chiba K, Hisaka A, Ishigami M, Kayama M, Mizuno N, Nagata Y, Takakuwa S, Tsukamoto Y, Ueda K, Kusuhara H, Ito K, Sugiyama Y. The intestinal first-pass metabolism of substrates of CYP3A4 and P-glycoprotein-quantitative analysis based on information from the literature. Drug Metab Pharmacokinet 2003 18 365-372. 

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