Pre-systemic metabolism

F. Y. Chung and M. D. Donovan. Nasal pre-systemic metabolism of peptide drugs Substance P metabolism in the sheep nasal cavity. Int J Pharm 128 229-237 (1996). 

Back DJ, Breckenridge AM, Maciver M, et al. The gut wall metabolism of ethinyloestradiol and its contribution to the pre-systemic metabolism of ethinyloestradiol in humans. Br J Clin Pharmacol 1982 13(3) 325-330. 

In summary, the advantages of IN delivery to the CNS are considerable. IN administration has been shown to improve the bioavailability of many pre-systemically metabolized drugs entering CNS, eliminating the need for systemic delivery and reducing unwanted systemic side effects. It is also rapid and noninva-sive. Furthermore, IN delivery does not require any modification of the therapeutic drugs and does not require the drugs to be coupled to any carriers. 

Pre-systemic metabolism the presence of enzymes, such as peptidases, esterases, in the skin might metabolise the drug into a form that is therapeutically inactive, thereby reducing the efficacy of the drug [21]... 

Patches based on GL and pectin hydrogels were described by Mazzitelli et al. (2013). Hydrogels are formed by taking advantage of the different gelling properties of pectin and gelatin (i.e., ionic and thermal gelation mechanisms), and proposed as transdermal formulations for the delivery of testosterone to overcome the limitation of its low bioavailability due to liver pre-systemic metabolism. 

In a second study (Walton et al. 2001b), the magnitude of the interspecies differences in the internal dose of compounds for which glucuronidation is the major pathway of metabolism in either humans or in the test species was determined. There were major interspecies differences in the nature of the biological processes that influence the internal dose including route of metabolism, the extent of pre-systemic metabohsm, and enterohepatic recirculation. There was also a wide variability in the magnitude of differences in the internal dose for all of the test species. The mean values for the clearance ratios compared to humans were 4.5 for the mouse, 9.1 for the rat, 8.7 for the rabbit, and 9.7 for the dog. Thus, the fourfold default factor was exceeded for aU the species. 

The medicinal and ceremonial uses of cocaine via coca leaves can be traced back over 4,000 years to pre-Columbian times. It continues to be used legally and is part of the daily culture of South American Indians. Coca leaves are chewed to combat fatigue and to ward off hunger. They are also used to alleviate problems of the larynx, digestive system, metabolism of carbohydrates, vertigo, altitude sickness, and for psychological ills. 

Inhaled drags intended for systemic action are likely to be subjected to some first-pass metabolism during their absorption from the lung. The extent of this pre-systemic first-pass metabolism in the lung has not been fully quantified for many drags but is estimated to be far less than that seen in the gastrointestinal tract and liver after oral dosing (see Section 6.3.3). 

High degree of pre-systemic and hepatic first-pass metabolism... 

HUMAN TOXICITY DATA oral-man TDLo 700mg/kg oral-man TDLo 50mg/kg toxic effect gastrointestinal tract oral-man TDLo 1430pg/kg toxic effect central nervous system oral-human LDLo 1400 mg/kg oral-woman TDLo 256g/kg/12W toxic effect central nervous system, endocrine system oral-woman TDLo 41g/kg (41 W pregnancy) toxic effect reproductive effects intrauterine-woman TDLo 200mg/kg (5D pre) toxic effect reproductive effects dna inhibition-human lymphocyte 220 mmol/L subcutaneous-infant LDLo 19,440 mg/kg toxic effect central nervous system, metabolic effects. 

Pre systemic elimination, membrane passage, first-pass metabolism, and appearance of the active substance in the systemic circulation (= biological availability)... 

An active substance generally exerts its effect through defined molecular interactions with a receptor. As a prerequisite, the substance needs to be dissolved and reach the receptor. For a local effect, the substance is usually administered in close proximity to the desired target and should penetrate into body tissues as little as possible. However, when a systemic effect is desired, the substance has to reach the blood circulation system for distribution. For extravascular administration routes, this requires membrane passage and may expose the substance to various pre systemic elimination mechanisms, including metabolism and efflux transporters such as P-glycoprotein. 

Cairns-Smith and Walkerl l propose reaction networks in which formaldehyde and glycolaldehyde are key intermediates. The different networks are considered phenotypes, formed by catalytic contact with clay minerals. Clays are proposed to play a role similar to DNA in replication. Replicating clays are thought to contain the genetic information (cation composition, distribution, imperfections, etc.) for pre-life metabolic systems. 

Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. The apparent elimination half-life of oxycodone following the administration of OxyContin was 4.5 hours compared to 3.2 hours for immediate-release oxycodone. About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a parenteral dose. This high oral bioavailability is due to low pre systemic and/or first-pass metabolism. 

Oxymorphone ER has an absolute bioavailability of approximately 10%. This bioavailability is thought to be primarily due to pre-systemic (first pass) metabolism in the liver [ 1 ]. Oxymorphone ER has a mean steady-state plasma concentration which linearly increases with dose [1]. The time to maximum concentration is estimated to be 25-90 minutes for all doses. Oxymorphone ER has a mean t, of9.35-11.30 hours for doses of 5-40... 

Recently, multidimensional GC has been employed in enantioselective analysis by placing a chiral stationary phase such as a cyclodextrin in the second column. Typically, switching valves are used to heart-cut the appropriate portion of the separation from a non-chiral column into a chiral column. Heil et al. used a dual column system consisting of a non-chiral pre-column (30 m X 0.25 mm X 0.38 p.m, PS-268) and a chiral (30 m X 0.32 mm X 0.64 p.m, heptakis(2,3-di-(9-methyl-6-(9-tert-butyldimethylsilyl)-(3-cyclodextrin) (TBDM-CD) analytical column to separate derivatized urinary organic acids that are indicative of metabolic diseases such as short bowel syndrome, phenylketonuria, tyrosinaemia, and others. They used a FID following the pre-column and an ion trap mass-selective detector following the... 

Ketoconazole (a potent inhibitor of CYP3A4) has been shown to increase the oral bioavailability of cyclosporin from 22 to 56% [50]. This consisted of a 1.8-fold decrease in systemic clearance combined with a 4.9-fold decrease in oral clearance. The authors estimated that hepatic extraction was decreased only 1.15-fold, whereas the oral bioavailability increased 2.6-fold and the observation was attributed to decreased intestinal metabolism. Erythromycin was also shown to increase the oral bioavailability of cyclosporin A 1.7-fold, while pre-treatment with rifampin (an inducer of CYP3A4) decreased oral bioavailability of cyclosporin from 27% to 10% due to a 4.2-fold increase in oral clearance but only a 1.2-fold increase in systemic clearance. Floren et al. [51] have also shown that ketoconazole can double the oral bioavailability of tacrolimus in man by inhibiting gut wall CYP3A4. 

Pre-Inoculation Steps Determination and optimization of an adaptive co-metabolic and symbiotic bio-products system to achieve both, hemicycle A (carboxylation/oxidative stage) and hemicycle B (decarboxylation/reductive stage), and of the sequence and timing of events in terms of bio-products inoculation to accomplish the RACDC. 

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