the stomach (pH 2–3) where carboxylic acids are mostly present in their undissociated form), it comes at the expense of passive permeability. The latter is particularly
prominent for anionic drugs owing to repulsive interactions with the negatively
charged head groups of the phospholipids constituting the lipid bilayer of cell
membranes.
4 Absorption, Distribution, Metabolism, and Excretion
(ADME)
The multi-parametric optimization of drug properties extends well beyond target
affinity, solubility, and permeability (not even considering the experimental evaluation of in vivo efficacy in disease model, off-target selectivity, or safety pharmacology!) with pharmacokinetic properties being a pivotal decision criterion for
defining compound quality. Although small-molecule drugs can be delivered locally
and systemically by different routes, including inhalation, subcutaneous and intramuscular injection, or dermal application, oral administration represents the single
most important delivery option. Once swallowed, the formulation reaches the highly
acidic environment of the stomach where release and dissolution of the active
ingredient usually take place. Following gastric emptying into the duodenum
(pH 5.5–7), the concentration gradient between the drug in the lumen and the
enterocytes as the epithelial cells lining the inner surface of the intestine drives the
absorption. Importantly, the fraction of dose absorbed in the intestine is largely
governed by the two aforementioned compound properties; for the compound to be
efficiently absorbed, it needs to be present in dissolved state and exhibit good
cellular permeability. When these two requirements are not properly addressed
during chemical design, the active is discharged from the body in altered form
through feces and thereby contributes directly to the drug burden in municipal
sewage.
After uptake into the enterocyte, the drug gets into the blood of the portal vein and
flows to the liver (weighing about 1.5 kg in an adult male) as the port of entry to
systemic circulation. Next to the physical barrier of the intestinal wall, this organ
represents the second barrier to the drug molecule on its way to the site of action
(unless it is the liver itself as in case of the family of statins acting on HMG-CoA
reductase). As a mechanism of natural protection from foreign substances of no
apparent beneficial value, the human liver has evolved over the course of evolution
to produce specific enzymes capable of metabolizing unwanted compounds. Synthetic drugs, but also potentially harmful drugs of natural origins, are recognized and
subject to metabolic reactions (see chapter “Metabolism of Pharmaceuticals in Plants
and their Associated Microbiota” for a more detailed description of drug metabolism) which convert the substrate into more polar and thereby more readily
excretable metabolites. This presystemic elimination is referred to as first-pass
metabolism and is in most instances an undesired process that needs to be strictly
10
N. Montemurro et al.
prominent for anionic drugs owing to repulsive interactions with the negatively
charged head groups of the phospholipids constituting the lipid bilayer of cell
membranes.
4 Absorption, Distribution, Metabolism, and Excretion
(ADME)
The multi-parametric optimization of drug properties extends well beyond target
affinity, solubility, and permeability (not even considering the experimental evaluation of in vivo efficacy in disease model, off-target selectivity, or safety pharmacology!) with pharmacokinetic properties being a pivotal decision criterion for
defining compound quality. Although small-molecule drugs can be delivered locally
and systemically by different routes, including inhalation, subcutaneous and intramuscular injection, or dermal application, oral administration represents the single
most important delivery option. Once swallowed, the formulation reaches the highly
acidic environment of the stomach where release and dissolution of the active
ingredient usually take place. Following gastric emptying into the duodenum
(pH 5.5–7), the concentration gradient between the drug in the lumen and the
enterocytes as the epithelial cells lining the inner surface of the intestine drives the
absorption. Importantly, the fraction of dose absorbed in the intestine is largely
governed by the two aforementioned compound properties; for the compound to be
efficiently absorbed, it needs to be present in dissolved state and exhibit good
cellular permeability. When these two requirements are not properly addressed
during chemical design, the active is discharged from the body in altered form
through feces and thereby contributes directly to the drug burden in municipal
sewage.
After uptake into the enterocyte, the drug gets into the blood of the portal vein and
flows to the liver (weighing about 1.5 kg in an adult male) as the port of entry to
systemic circulation. Next to the physical barrier of the intestinal wall, this organ
represents the second barrier to the drug molecule on its way to the site of action
(unless it is the liver itself as in case of the family of statins acting on HMG-CoA
reductase). As a mechanism of natural protection from foreign substances of no
apparent beneficial value, the human liver has evolved over the course of evolution
to produce specific enzymes capable of metabolizing unwanted compounds. Synthetic drugs, but also potentially harmful drugs of natural origins, are recognized and
subject to metabolic reactions (see chapter “Metabolism of Pharmaceuticals in Plants
and their Associated Microbiota” for a more detailed description of drug metabolism) which convert the substrate into more polar and thereby more readily
excretable metabolites. This presystemic elimination is referred to as first-pass
metabolism and is in most instances an undesired process that needs to be strictly
10
N. Montemurro et al.