Factors affecting drug distribution Organ blood flow:high and low perfusion organs Plasma protein binding:saturability(<10 to ~99%),competitive inhibition Molecular size,lipid solubility Barriers:blood-brain barrier,placenta barrier, blood-eye barrier Drug metabolism-Phase I Phase I biotransformation involves oxidation, reduction and hydrolysis The active site of cytochrome P-450: Steps of the reaction: Drug substrate binds to P450 P-450-drug complex is reduced by NADPH Molecular oxygen (binds to reduced P-450- drug complex Oxygen is reduced to an "activated"state One atom of oxygen combines with the drug substrate,the other atom forms water The enzyme complex dissociates to yield free oxygenated drug metabolite Stoichiometry of the reaction: DH+NADPH+O2 DOH+NADP'+H2OFactors affecting drug distribution • Organ blood flow: high and low perfusion organs • Plasma protein binding: saturability (<10 to   ~99%), competitive inhibition • Molecular size, lipid solubility • Barriers: blood‐brain barrier, placenta barrier, blood‐eye barrier Drug metabolism – Phase I • Phase I biotransformation involves oxidation, reduction and hydrolysis • Involves cytochrome p450 (CYP, mono‐ oxygenase system)