Principle of Medicinal Chemistry Notes

Drug Absorption Definition: The transport of unmetabolized drugs from the administration site to the systemic circulation.
Primary Physicochemical Factors: Lipophilicity and solubility are the critical determinants of absorption rate and extent (Leahy et al., 1989).
Cellular Barrier: The gastrointestinal epithelial membrane consists of a lipid bilayer; transcellular passage depends on the drug's ability to penetrate this lipid layer.
Lipophilicity Studies:
- Schanker (1960) demonstrated that barbiturate absorption increases with lipophilicity.
- Taylor et al. showed a correlations between lipophilicity and absorption rates for beta-blockers in rat small intestines.

Amine Influence: Many effective drugs contain amine groups with a $pKa$ between $6$ and $8$ . This allows them to exist in equilibrium between ionized (water-soluble) and non-ionized (lipid-soluble) forms at physiological pH.
Henderson–Hasselbalch Equation:

$pH = pKa + \log\left(\frac{[RNH_2]}{[RNH_3^+]}\right)$

Equilibrium: When a drug is $50\%$ ionized, the $pH$ equals the $pKa$ .
Ion Trapping: The accumulation of drugs on one side of a membrane due to a $pH$ gradient.
- Acidic drugs accumulate in alkaline environments (e.g., urine).
- Basic drugs (e.g., morphine) are secreted into the acidic stomach.
- Sodium bicarbonate increases amphetamine (weak base) absorption in the stomach and reduces its urinary excretion.

Passive Lipid Diffusion: The primary mechanism where molecules move from high to low concentration. Driven by Fick's Law:

$\text{Rate} = \frac{D \times A \times P \times (C_{out} - C_{in})}{h}$

Aqueous Diffusion: Occurs through channels for molecules usually less than $150-200\,MW$ ; capillary pores allow larger molecules ( $20,000-30,000\,MW$ ) except in the brain.
Carrier-Mediated Transport: Facilities movement for analogs of endogenous compounds.
Vesicular Transport: Includes endocytosis (into cell), exocytosis (out of cell), and transcytosis (across cell).

Volume of Distribution ( $V_d$ ): A theoretical volume quantifying drug distribution:

$V_d = \frac{Ab}{Cp}$

Plasma Protein Binding: Only free (unbound) drugs can reach tissues or exert pharmacological effects.
- Albumin: Primarily binds acidic and neutral drugs.
- Alpha-1 acid glycoprotein: Primarily binds basic drugs.
- Sequestration: Binding rates above $90\%$ significantly alter tissue distribution; above $95\%$ creates high risk for toxicity if displaced.

Definitions: Xenobiotic metabolism modifies foreign structures to increase hydrophilicity for easier excretion.
Phases of Metabolism:
- Phase 0: Liver uptake via influx transporters (e.g., OATPs).
- Phase I: Functionalization (oxidation, reduction, hydrolysis). Primarily mediated by Cytochrome P450 (CYP).
- Phase II: Conjugation with polar groups.
- Phase III: Efflux transport out of cells.
Cytochrome P450 (CYP): Heme-thiolate monooxygenases ( $50-60\,kD$ ). Major liver isoforms include CYP3A4, 2C9, 2C8, 2E1, and 1A2.
First-Pass Effect: Metabolism in the liver or gut wall before the drug reaches systemic circulation, common in drugs with a high hepatic extraction ratio (E > 0.7).

Glucuronidation: Catalyzed by UDP–glucuronosyltransferases (UGTs); uses UDP-glucuronic acid (UDPGA) as a co-substrate.
Sulfoconjugation: Catalyzed by sulfotransferases (SULTs); uses 3’-phosphoadenosine-5’-phosphosulfate (PAPS) as the sulfonate donor.
Glutathionylation: Catalyzed by glutathione S–transferases (GSTs); protects against oxidative stress and reactive electrophiles.
Acetylation: Uses Acetyl-CoA; common for primary amines and hydrazines.
Methylation: Uses S-Adenosyl methionine (SAM) as the methyl donor.
Amino Acid Conjugation: Example includes glycine conjugation of benzoic acid to form hippuric acid (discovered in 1841 by Alexander Ure).

Major Routes: Urine, bile, feces, and respiration. The kidney is the primary organ for excretion via glomerular filtration and tubular secretion.
Clearance ( $CL$ ): Efficiency of drug removal:

$CL = \frac{\text{Rate of elimination}}{Cp}$

Plasma Half-life ( $t_{1/2}$ ): Time required for plasma concentration to decrease by $50\%$ . It takes $4-5$ half-lives to reach a steady state ( $Cp,ss$ ) or complete elimination:

$t_{1/2} = \frac{0.693 \times V_d}{CL}$

Prodrugs: Inactive molecules converted in vivo to active parent drugs to overcome barriers like limited solubility or poor permeability (e.g., Aspirin, Methenamine).
Soft Drugs: Active compounds designed for rapid deactivation and detoxification after fulfilling their therapeutic role to minimize systemic toxicity.
Hard Drugs: Metabolically stable compounds that are excreted unchanged.
Codrugs (Mutual Drugs): Two active drugs coupled together, each acting as the promoiety for the other (e.g., Sultamicillin).