Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations. Sheila Annie Peters

for DDI. Pharmacokinetics Aim for linear PK by keeping the dose as low as possible. To minimize uncertainty in predictions of disposition.

1.5.1 Pharmacological Targets and Drug Action

A pharmacological effect often involves the modulation of an intrinsic physiological process by a drug that binds to a target protein. Pharmacological targets can be receptors and proteins involved in regulatory pathways, enzymes, structural proteins, nuclear receptors, transporter proteins, or ion channels (Table 1.5). Drugs may be classified depending on how they modulate their receptor and achieve drug effect. A drug is said to be an agonist (Figure 1.12) or partial agonist (Figure 1.13) if it binds to a receptor and functionally mimics or enhances the action of an endogenous ligand. by stimulating receptor activity fully or partially. Partial agonism may be explained by either an inefficient modulation of receptor conformation/transduction following receptor occupancy or by a higher drug affinity to the inactive form of a receptor, that isomerizes between an active and an inactive form. A drug that reduces receptor activity through competing with the endogenous agonist for the same active site is called a competitive antagonist. A drug is said to be a noncompetitive antagonist if it blocks or inhibits the pharmacological response of an endogenous agonist, by binding to a different site and triggering a conformational change in the receptor protein. A drug that binds to a target irreversibly (e.g., covalent binding) is called an irreversible inhibitor. Both noncompetitive and irreversible inhibitors decrease the receptor count that is available for the endogenous agonist, thereby reducing its efficacy. Inverse agonists appear to act in an opposite manner to agonists at a receptor site. Unlike an agonist which increases receptor activity, or an antagonist which blocks its activity, an inverse agonist reverses the activity of constitutively active receptors that are coupled to second messenger pathways even in the absence of an agonist. The binding of a drug to a target protein can initiate several direct or indirect responses depending on the type of target protein, its location, and target class (Figure 1.14). Most enzyme inhibitions lead to direct effect. Examples of indirect drug responses include the release of hormones and/or other endogenous ligands to stimulate a particular response or the activation of a second messenger which, in turn, initiates a series of biochemical reactions (e.g., drug binding to a G‐protein coupled receptor, GPCR) leading to the desired response.

TABLE 1.5. Classes of Pharmacological Targets

Pharmacological Target Class	Examples of Targets	Location	Endogenous Ligands	Type of Drug
G‐protein‐coupled receptors (GPCRs)	Adrenoreceptor, metabotropic neurotransmitter receptors (metabotropic glutamate receptors or mGluRs, muscarinic acetylcholine receptors, GABA‐B receptor, 5HT1, 5HT2), CCR, opioid, NK	Transmembrane, cell surface or intracellular	Neurotransmittersa and hormonesb	Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist.
Receptor tyrosine kinase	EGF, VEGF, PDGF, FGF, HGF, TIE, Trk, MuSK, RYK, and insulin receptor families	Cell surface	Growth factors,c insulin	Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist.
Guanylyl cyclase receptors	GC‐A, GC‐B, GC‐C	Cell surface	Guanosine‐5′‐triphosphate (GTP)	Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist.
Nuclear receptors	Thyroid hormone‐like, estrogen‐like, glucocorticoid receptors, PPAR, FXR, LXR, and other orphan receptors	Cytosol or translocated to nucleus	Retinoic acid, vitamin D3, hormones	Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist.
Ligand‐gated ion channels or ionotropic receptors	Glutamate cationic receptor, nicotinicoid receptor (5‐HT3, nicotinic acetylcholine receptor, GABA‐A)	Synapses	Neurotransmitters	Competitive, noncompetitive, and irreversible antagonist, agonists, partial agonist, or inverse agonist.
Voltage‐gated ion channels	NaV, KV, and CaV	Transmembrane ion channels found along the axon and at the synapse in neurons and in other cells	Respond to changes in voltage	Blocker, inhibitor
Enzymes and factors	Transferases such as RNA directed DNA‐polymerase; oxidoreductases such as HMG‐CoA reductase and cyclooxygenases	Cell surface, intracellular, or membrane spanning	Large variety of endogenous and exogenous substrates	Inhibitor activator
	Peptidases such as ACE, trypsin, thrombin, clotting factors, renin, HIV protease, cathepsin, and caspase
Structural proteins	α,β,γ,δ, and ε tubulin	Extracellular or intracellular	GTP	Inhibitor

^a Neurotransmitters are amino acids such as glutamate, aspartate, serine, GABA, and glycine; monoamines such as dopamine, 5‐HT, adrenaline, noradrenaline, and melatonin; neuropeptides; acetylcholine, adenosine, histamine, anadamide, etc.

^b Hormones could be derivatives of the amino acids tyrosine and tryptophan. Examples are catecholamines and thyroxine. Peptide hormones consist of chains of amino acids. Examples are TRH and vasopressin. Examples of protein hormones include insulin and growth hormone. More complex protein hormones bear carbohydrate side chains and are called glycoprotein hormones. Luteinizing hormone, follicle‐stimulating hormone, and thyroid‐stimulating hormone are examples of glycoprotein hormones. Lipid and phospholipid‐derived hormones are derivatives of lipids such as linoleic acid and arachidonic acid and phospholipids. Steroid hormones are derived from cholesterol and eicosanoids. Examples of steroid hormones are testosterone and