Liver first-pass effect

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]. 

The liver is also the principal metabolic center for hydrophobic amino acids, and hence changes in plasma concentrations or metabolism of these molecules is a good measure of the functional capacity of the liver. Two of the commonly used aromatic amino acids are phenylalanine and tyrosine, which are primarily metabolized by cytosolic enzymes in the liver [1,114-117]. Hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase is very efficient by the liver first pass effect. In normal functioning liver, conversion of tyrosine to 4-hy-droxyphenylpyruvate by tyrosine transaminase and subsequent biotransformation to homogentisic acidby 4-hydroxyphenylpyruvic acid dioxygenase liberates CO2 from the C-1 position of the parent amino acid (Fig. 5) [1,118]. Thus, the C-1 position of phenylalanine or tyrosine is typically labeled with and the expired C02 is proportional to the metabolic activity of liver cytosolic enzymes, which corresponds to functional hepatic reserve. Oral or intravenous administration of the amino acids is possible [115]. This method is amenable to the continuous hepatic function measurement approach by monitoring changes in the spectral properties of tyrosine pre- and post-administration of the marker. 

There is no first-pass effect (this can lead to intoxication or detoxification) apart from the liver, first-pass effects may also be of relevance with regard to the lung and the skin. 

The nasal route of drug delivery avoids the liver first-pass effect, but the pseudo-first-pass effect owing to nasal metabolism of drugs is still a concern. Many enzymes such as carboxylesterase, aldehyde dehydrogenase, glutathione transferases, UDP-glucoronyl transferase, epoxide hydrolases, CYP-dependent monoxygenases, exo- and endopeptidases and proteases are present in the nasal mucosa.106 108,110,116 CYP enzymes are present abundantly in the olfactory epithelium.107,110... 

D. K. F. Meijer and P. J. Swart, Isolated perfused liver as a tool to study the disposition of peptides, liver first-pass effects, and cell-specific drug delivery, J. Contr. Rel. 46 139-156 (1997). 

Metabolism 5% metabolised by the liver First-pass effect Hepatocyte dependent Prodrug CYPs Active metabolites Genetics... 

Figure 12.1 Schematic representation of gut wall and liver first-pass effects.

Figure 9.1 An oral dmg leaving the intestinal lumen and passing the first barrier to entry into the body by either entering the apical membrane of enteroc5des or by passing paracellularly between them is considered absorbed. Administered drug that gets absorbed and is able to survive metabolism in the gut wall and excretion by the liver (first pass effect), finally reaching its site of action is considered bioavailable in the strict sense. But in practice, bioavailability is usually determined using dmg concentrations in systemic circulation. ...

Active substances imdergoing substantial metabolism when passing the intestine and/or liver (first-pass effect) show a limited bioavailabUity, often with large intra- and inter-individual differences. 

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