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First-pass metabolism may occur in the liver (for propranolol, lidocaine, clomethiazole, and nitroglycerin) or in the gut (for benzylpenicillin and insulin). [4] The four primary systems that affect the first pass effect of a drug are the enzymes of the gastrointestinal lumen, [5] gastrointestinal wall enzymes, [6] [7] [8] bacterial enzymes [5] and hepatic enzymes.
Due to the first pass through the liver, disproportionate and supraphysiological levels of estrogens occur locally in the liver with oral estradiol. [ 117 ] [ 12 ] These levels are approximately 4- to 5-fold higher than in the circulation, based on differences in hepatic estrogenic potency for oral estradiol relative to transdermal estradiol.
Enterohepatic circulation of drugs. Enterohepatic circulation is the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver.
Furthermore, after absorption from the gastrointestinal tract, such drugs must pass to the liver, where they may be extensively altered; this is known as the first pass effect of drug metabolism. Due to the digestive activity of the stomach and intestines, the oral route is unsuitable for certain substances, such as salvinorin A
By definition, when a medication is administered intravenously, its bioavailability is 100%. [ 2 ] [ 3 ] However, when a medication is administered via routes other than intravenous, its bioavailability is lower due to intestinal epithelium absorption and first-pass metabolism .
In particular, the oral route is subject to a high first-pass effect, which results in high levels of testosterone in the liver and consequent hepatic androgenic effects, as well as low potency due to first-pass metabolism in the intestines and liver into metabolites like dihydrotestosterone and androgen conjugates. [2]
In addition, the rectal route bypasses around two-thirds of the first-pass metabolism as the rectum's venous drainage is two-thirds systemic (middle and inferior rectal vein) and one-third hepatic portal system (superior rectal vein). This means the drug will reach the circulatory system with significantly less alteration and in greater ...
Conversely, if it is absorbed by the upper portion of the rectum, progesterone is subject to hepatic first-pass metabolism due to entry into the hepatic portal system via the superior rectal vein. [18] As such, although rectal administration is a parenteral route, it may still be subject to some first-pass metabolism similarly to oral ...