controlled whenever high blood concentrations are necessary to achieve the desired
pharmacological effect.
Once in systemic circulation, provided that the drug is sufficiently membrane
permeable, it is distributed to all organs and tissues until an equilibrium is achieved
where the rate of transfer into tissues equals the rate of back-diffusion into blood.
The extent of this distribution is dependent on the partition coefficient (K p ) between
tissue/organ and blood which in turn is a function of the affinity of the compound for
plasma proteins on the one hand and non-specific binding to tissue components on
the other. The pharmacokinetic parameter that quantitatively describes this property
of a drug is the volume of distribution, V d (in units of L/kg), with a high value
indicating extensive tissue distribution [8]. Apart from lipophilicity, the compound
property with the largest effect on V d is the ion class: the low V d of acids arises from
strong binding to albumin as the most abundant plasma protein (4–5%) with
numerous basic amino acids available for electrostatic interactions [9]. A further
contributing factor to the low V d of acidic drugs is the repulsion by phospholipidbased membranes of tissue cells. Basic compounds, in turn, display a pronounced
affinity for tissues (pH range: 7.1–7.4) because they are, in least in part, protonated
under these settings which allows for strong interaction with the negatively charged
phospholipids. At a macroscopic level, this translates into a high partition coefficient
with total tissue concentrations exceeding those measured in blood [10]. When
interpreting partition coefficients, however, it is crucial to understand that a high
K p is not indicative of tissue accumulation but the consequence of non-specific
binding to tissue components; in other words, total tissue concentrations provide
very limited information and do not allow to infer the actual unbound concentration
potentially triggering off-target pharmacological responses. This fundamental concept helps explain the high tissue-specific K p ´s of sertraline reported for vertebrates
exposed to this highly lipophilic base (logP: 5.15).
The two major eliminatory processes contributing to the removal of drug from the
bloodstream are renal and biliary excretion of the unchanged parent compound and
hepatic metabolism. As a simple rule, polar drugs of small size (logD < 0) are
excreted with relative ease into urine through glomerular filtration at the nephron,
whereas large molecules with high TPSA are amenable to biliary excretion, which
drains the compound through the bile duct into the intestine for excretion alongside
feces [11, 12]. The major elimination mechanism for the majority of marketed drugs,
however, is enzyme-mediated biotransformation giving rise to drug
metabolites [13].
Given the diversity and substrate selectivity of drug-metabolizing enzymes,
particularly in the liver as the predominant site of drug metabolism, a molecule
can undergo a variety of reactions generating metabolites with an inherent chance of
being excreted into human wastes. With the ultimate goal of maximizing human
exposure at the lowest possible dose, identification of the site of metabolism within a
discovery compound and chemical design to improve the metabolic stability in the
next generation of compounds is one of the principal tasks of dedicated ADME
scientists who work closely together with medicinal chemists. The fact that commonly tens to hundreds of compounds need to be screened in oral drug discovery
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
11
pharmacological effect.
Once in systemic circulation, provided that the drug is sufficiently membrane
permeable, it is distributed to all organs and tissues until an equilibrium is achieved
where the rate of transfer into tissues equals the rate of back-diffusion into blood.
The extent of this distribution is dependent on the partition coefficient (K p ) between
tissue/organ and blood which in turn is a function of the affinity of the compound for
plasma proteins on the one hand and non-specific binding to tissue components on
the other. The pharmacokinetic parameter that quantitatively describes this property
of a drug is the volume of distribution, V d (in units of L/kg), with a high value
indicating extensive tissue distribution [8]. Apart from lipophilicity, the compound
property with the largest effect on V d is the ion class: the low V d of acids arises from
strong binding to albumin as the most abundant plasma protein (4–5%) with
numerous basic amino acids available for electrostatic interactions [9]. A further
contributing factor to the low V d of acidic drugs is the repulsion by phospholipidbased membranes of tissue cells. Basic compounds, in turn, display a pronounced
affinity for tissues (pH range: 7.1–7.4) because they are, in least in part, protonated
under these settings which allows for strong interaction with the negatively charged
phospholipids. At a macroscopic level, this translates into a high partition coefficient
with total tissue concentrations exceeding those measured in blood [10]. When
interpreting partition coefficients, however, it is crucial to understand that a high
K p is not indicative of tissue accumulation but the consequence of non-specific
binding to tissue components; in other words, total tissue concentrations provide
very limited information and do not allow to infer the actual unbound concentration
potentially triggering off-target pharmacological responses. This fundamental concept helps explain the high tissue-specific K p ´s of sertraline reported for vertebrates
exposed to this highly lipophilic base (logP: 5.15).
The two major eliminatory processes contributing to the removal of drug from the
bloodstream are renal and biliary excretion of the unchanged parent compound and
hepatic metabolism. As a simple rule, polar drugs of small size (logD < 0) are
excreted with relative ease into urine through glomerular filtration at the nephron,
whereas large molecules with high TPSA are amenable to biliary excretion, which
drains the compound through the bile duct into the intestine for excretion alongside
feces [11, 12]. The major elimination mechanism for the majority of marketed drugs,
however, is enzyme-mediated biotransformation giving rise to drug
metabolites [13].
Given the diversity and substrate selectivity of drug-metabolizing enzymes,
particularly in the liver as the predominant site of drug metabolism, a molecule
can undergo a variety of reactions generating metabolites with an inherent chance of
being excreted into human wastes. With the ultimate goal of maximizing human
exposure at the lowest possible dose, identification of the site of metabolism within a
discovery compound and chemical design to improve the metabolic stability in the
next generation of compounds is one of the principal tasks of dedicated ADME
scientists who work closely together with medicinal chemists. The fact that commonly tens to hundreds of compounds need to be screened in oral drug discovery
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
11