Presystemic elimination

The drug permeates through the epithelial barrier of the gut into the enterocyte however, a P-glycoprotein transports it back into the intestinal lumen. As a result, the amount actually absorbed can be greatly diminished. This counter-transport can vary interindividually for an identical substance and moreover may be altered by other drugs. 

En route from the intestinal lumen to the general circulation, the ingested substance is broken down enzymatically, e.g., by cytochrome P450 oxidases. 

Luellmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms 

The processes referred to under (2a, b) above are subsumed under the term presystemic elimination.  

In certain therapeutic situations, rapid presystemic elimination may be desirable. An important example is the use of glucocorticoids in the treatment of asthma. Because a significant portion of inhaled drug is swallowed, glucocorticoids with complete presystemic elimination entail only a minimal systemic load for the organism (p.340). The use of acetylsalicylic acid for inhibition of thrombocyte aggregation (see p.155) provides an example of a desirable presystemic conversion. 

---

Lee KM, Bruckner JV, Muralidhara S, et al. 1996. Characterization of presystemic elimination of trichloroethylene and its nonlinear kinetics in rats. Toxicol Appl Pharmacol 139 262-271. 

The impact of presystemic elimination may be clearly understood by considering the following relationships among the several steps involved in making the drug available to the systemic circulation. The significance of this relationship is its multiplicative nature, since most of the processes are sequential. These relationships assume linear or first-order kinetics (i.e., there is no nonlinearity or saturation effects). 

Bioavailability is defined as the fraction of a given drug dose that reaches the circulation in unchanged form and becomes available for systemic dis-tributioa The larger the presystemic elimination, the smaller is the bioavailability of an orally administered drug. 

Presystemic elimination refers to the fraction of drug absorbed that is excluded from the general circulation by biotransformation or by first-pass binding. 

Presystemic elimination diminishes the bioavailability of a drug after its oral administration. Absolute bioavailability = systemically available amount/ dose administered relative bioavailability = availability of a drug contained in a test preparation with reference to a standard preparation. 

The chemical structure of p-block-ers also determines their pharmacokinetic properties. Except for hydrophilic representatives (atenolol), p-sympatho-lytics are completely absorbed from the intestines and subsequently undergo presystemic elimination to a major extent (A). 

Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy. 

For sustained daytime angina prophylaxis, nitrates are of limited value because "nitrate pauses of about 12 h are appropriate if nitrate tolerance is to be avoided. If attacks occur during the day, ISDN, or its metabolite isosorbide mononitrate, may be given in the morning and at noon (e.g ISDN 40 mg in extended-release capsules). Because of hepatic presystemic elimination, NTG is not suitable for oral administratioa Continuous delivery via a transdermal patch would also not seem advisable because of the potential development of tolerance. With molsidomine, there is less risk of a nitrate tolerance however, due to its potential carcinogenicity, its clinical use is restricted. 

It is a potent and long acting opioid with partial mu receptor agonist property. 25 times more potent than morphine. Effects are similar to morphine but constipation is less marked. It undergoes extensive presystemic elimination and therefore is... 

Uno T, Ohkubo T, Sugawara K, Higashiyama A, Motomura S, Ishizaki T. Effects of grapefruit juice on the stereoselective disposition of nicardipine in humans evidence for dominant presystemic elimination at the gut site. Eur J Clin Pharmacol 2000 56(9-10) 643-649. 

Nitroglycerin (NTC) is distinguished by a high membrane penetrability and very low stability. It is the drug of choice in the treatment of angina pectoris attacks. For this purpose, it is administered as a spray, or in sublingual or buccal tablets for transmucosal delivery. The onset of action is between 1 and 3 minutes. Due to a nearly complete presystemic elimination, it is poorly suited for oral administration. Transdermal delivery (nitroglycerin patch) also avoids presystemic elimination. 

Tranylcypromine causes irreversible inhibition of the two isozymes MAOa and 0 2% Therefore, presystemic elimination in the liver of biogenic amines, such as tyramine, that are ingested in food (e. g., in aged cheese and Chianti) is impaired (with danger of a diet-induced hypertensive crisis). The compound is obsolete in some countries. 

---