First pass effect

Diclofenac is an exceedingly potent COX inhibitor slightly more efficacious against COX-2 than COX-1. Its absorption from the gastrointestinal tract varies according to the type of pharmaceutical formulation used. The oral bioavailability is only 30-80% due to a first-pass effect. Diclofenac is rapidly metabolised (hydroxylation and conjugation) and has a plasma half-life of 1.5 h. The metabolites are excreted renally and via the bile. 

Kwan, K.C. (1997) Oral BioavaUabUity and the First Pass Effect. Drug Metabolism and Disposition, 25(12), 1329-1336. 

From an analysis of the key properties of compounds in the World Dmg Index the now well accepted Rule-of-5 has been derived [25, 26]. It was concluded that compounds are most Hkely to have poor absorption when MW>500, calculated octanol-water partition coefficient Clog P>5, number of H-bond donors >5 and number of H-bond acceptors >10. Computation of these properties is now available as a simple but efficient ADME screen in commercial software. The Rule-of-5 should be seen as a qualitative absorption/permeabiHty predictor [43], rather than a quantitative predictor [140]. The Rule-of-5 is not predictive for bioavail-abihty as sometimes mistakenly is assumed. An important factor for bioavailabihty in addition to absorption is liver first-pass effect (metaboHsm). The property distribution in drug-related chemical databases has been studied as another approach to understand drug-likeness [141, 142]. 

An alternative to the oral route is the buccal mucoadhesive system. The Striant buccal system adheres to the inside of the mouth and the testosterone is absorbed through the oral mucosa and delivered to the systemic circulation. There is no first-pass effect, as the liver is bypassed by this route of administration. Patients apply a 30-mg tablet to the upper gum twice daily. The cost is similar to that of the patch or gel. Side effects unique to this dosage form include oral irritation, bitter taste, and gum edema. 

The fraction of the orally administered dose that is bioavailable to the systemic circulation (Fsystemjc) is dependent upon the fraction of the dose that is released from the dosage form (/released), multiplied by the fraction that is absorbed into the portal circulation on its way to the liver (/absorbed this is the fraction that escapes gut metabolism), multiplied by the fraction of the dose that escapes the hepatic first-pass effect (/hepatic)- Since this is a multiplicative process if, for... 

Fig. 2 Various routes and pathways by which a drug may be input into the body. The position of one lung is distorted to emphasize that the lungs are in an excellent position for cleansing the blood. The diagram is especially useful in explaining the first-pass effect following oral dosing, for which drug absorbed from the small intestine or stomach must first pass through the liver and, therefore, is subject to metabolism or biliary excretion before reaching the sampleable blood. (From Ref. 2.)...

This might be called a lung first-pass effect. ... 

Thus, if the hepatic clearance for a drug is largely relative to the hepatic blood flow, the extent of availability for this drug will be low when it is given by a route that yields first-pass effects. The decrease in availability is a function of only the anatomical site... 

The transdermal route of drug administration offers several advantages over other methods of delivery. For some cases, oral delivery may be contraindicated, or the drug may be poorly absorbed. This would also include situations for which the drug undergoes a substantial first-pass effect [173] and systemic therapy is desired. 

The first-pass effect has not been extensively evaluated in infants and children. The maturational rate of metabolic pathways would be directly related to the oral bioavailability of a drug subject to first-pass effect. Drugs that undergo glucuronidation during en-terohepatic recirculation may have altered systemic availability in children up to approximately 3 years of age because of delayed maturation of conjugation. 

M. L. Chen and A. J. Jackson, The role of metabolites in bioequivalency assessment, I. Linear pharmacokinetics without first pass effect, Pharm. Res, 8, 25 (1991). 

Current estimates suggest that there are around 30,000 alcohol-related deaths a year in the UK. The NHS (National Health Service) spends over 164m a year treating alcohol-related conditions, and one in four male hospital beds is occupied by someone with an alcohol-related illness. Alcohol adversely aflfects numerous aspects of health, even in those who are only moderate drinkers. However, the effects of high volumes over long periods are certainly the most serious and life-threatening. Alcohol passes through the stomach and small intestine and is then absorbed into the blood stream from where it is metabolised by the liver (the first-pass effect Chapters 3 and 9). 

First-pass effect (metabolism) The metabolism of a drug when it first passes through the liver. This is one of the major determinants of bioavailability for orally administered drugs. 

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