Principles of Medicinal Chemistry: Pharmacokinetics and Drug Metabolism

Definition: Drug absorption is the transport of an unmetabolized drug from the site of administration to the systemic circulation.
Primary Factors: Lipophilicity and solubility are the most critical physicochemical factors affecting the rate and extent of absorption (Leahy et al., 1989).
Epithelial Barrier: The gastrointestinal (GI) membrane is a lipid bilayer; transcellular passage depends on a drug's ability to penetrate these tightly packed phospholipids.
The Amine Advantage: Many effective drugs contain amine groups with a $pKa$ of $6\text{--}8$ . This allows them to exist in equilibrium between ionized (water-soluble/active binding) and non-ionized (lipid-soluble/membrane-crossing) forms at biological pH.

Henderson-Hasselbalch Equation: Used to determine the extent of ionization at a specific $pH$ . * For weak bases: $pH = pKa + \log\left(\frac{[RNH_2]}{[RNH_3^+]}\right)$ . * When $pH = pKa$ , the drug is $50\%$ ionized.
Biological pH Variations: * Gastric Juice: $pH \, 1.5\text{--}4.0$ . * Intestine: $pH \, 7.0\text{--}8.5$ . * Blood: $pH \, 7.35\text{--}7.45$ .
Ion Trapping: The accumulation of a drug on the side of a membrane where the $pH$ favors its ionized form. * Acidic drugs accumulate in alkaline environments (e.g., urine). * Basic drugs accumulate in acidic environments (e.g., morphine in gastric juice).

Passive Lipid Diffusion: The primary mechanism for drug passage; molecules move down a concentration gradient. It is described by Fick's Law: $Rate = \frac{D \times A \times P \times (C_{out} - C_{in})}{h}$
Passive Aqueous Diffusion: Occurs through aqueous channels for small molecules ( $< 200\,MW$ ). Capillary linings allow larger molecules ( $20,000\text{--}30,000\,MW$ ).
Facilitated Diffusion: Carrier-mediated transport down a gradient without energy requirement.
Active Transport: Requires $ATP$ to move substances against a concentration gradient via specific proteins.
Vesicular Transport: Includes endocytosis (into cell), exocytosis (out of cell), and transcytosis (across cell).

Bioavailability ( $F$ ): The fraction of an oral dose reaching the systemic circulation. It is reduced by the "First-Pass Effect" (metabolism in the liver and gut wall).
Volume of Distribution ( $V_d$ ): A theoretical volume quantifying drug distribution extent: $V_d = \frac{A_b}{C_p}$ where $A_b$ is the amount of drug in the body and $C_p$ is the plasma concentration.
Plasma Protein Binding (PPB): Only the free (unbound) drug is pharmacologically active and available for metabolism/excretion. * Albumin: Primary binder for acidic and neutral drugs. * Alpha-1 Acid Glycoprotein: Primary binder for basic drugs.

Phase 0: Influx (uptake) transporters (e.g., OATPs) move the drug into the cell.
Phase I: Introduction of reactive or polar groups via oxidation, reduction, or hydrolysis.
Phase II: Conjugation reactions that attach polar groups to increase hydrophilicity for excretion. * Glucuronidation: Uses $UDP$ -glucuronic acid ( $UDPGA$ ) and $UGT$ enzymes. * Sulfoconjugation: Uses $3'-phosphoadenosine-5'-phosphosulfate$ ( $PAPS$ ) and sulfotransferases. * Glutathionylation: Conjugation with glutathione ( $GST$ enzymes) for detoxification and protection against oxidative stress.
Phase III: Efflux transporters pump metabolites out of the cell.

Function: Heme-thiolate monooxygenases responsible for the oxidative metabolism of $70\text{--}80\%$ of clinical drugs.
Nomenclature: Classified into families (e.g., $CYP3$ ), subfamilies ( $CYP3A$ ), and individual enzymes ( $CYP3A4$ ).
Variability Factors: * Polymorphism: Genetic variations leading to poor, intermediate, extensive, or ultrarapid metabolizer phenotypes (e.g., $CYP2D6$ , $CYP2C19$ ). * Induction: Xenobiotics increase enzyme expression, lowering drug plasma levels. * Inhibition: Drugs or toxins block enzyme activity, increasing potential for toxicity.

Clearance ( $CL$ ): The volume of plasma cleared of drug per unit time ( $CL_{total} = CL_{renal} + CL_{hepatic} + CL_{others}$ ).
Plasma Half-Life ( $t_{1/2}$ ): Time for concentration to drop by $50\%$ . It typically takes $4\text{--}5$ half-lives to reach a steady state ( $C_{pss}$ ) or eliminate a drug.
Renal Excretion: Involves glomerular filtration, active tubular secretion, and passive reabsorption.

Prodrugs: Pharmacologically inactive compounds converted to the active form in vivo to overcome barriers like poor solubility or permeability.
Soft Drugs (Antedrugs): Active compounds designed to be rapidly deactivated into non-toxic metabolites after therapeutic action to minimize systemic exposure.
Hard Drugs: Active compounds that are not metabolized and are excreted unchanged, minimizing toxic metabolite risks.
Codrugs (Mutual Drugs): Two active drugs coupled together, where each acts as the promoiety for the other (e.g., sultamicillin).

Partition Coefficient ( $P$ ): Ratio of concentrations in a biphasic system (usually n-octanol/water) for neutral species.
Distribution Coefficient ( $D_{pH}$ ): A $pH$ -dependent descriptor for ionizable solutes: $\log(D_{pH}) = \log(P) + \log(f_N)$ where $f_N$ is the molar fraction of the neutral form.
Hydrophobic Effect: The entropy-driven process where water molecules become less ordered as apolar moieties cluster together.