Lecture 1 and 2 - Drug Metabolism PDF

Medicinal Chemistry I PC508 Lecture 1 Dr/ Mohammed T.El-Saadi Ass.Prof Of Medicinal Chemistry Faculty of Pharmacy Sinai University. Pharmacokinetic (ADME) properties to study what the body dose to drug It’s a must for medicinal chemist to stud...

Medicinal Chemistry I PC508 Lecture 1 Dr/ Mohammed T.El-Saadi Ass.Prof Of Medicinal Chemistry Faculty of Pharmacy Sinai University. Pharmacokinetic (ADME) properties to study what the body dose to drug It’s a must for medicinal chemist to study drug absorption, distribution, metabolism, elimination at an early stage. Pharmacodynamic properties to study what the drug dose to the body The study of the physiological response, mechanism of drug action and dose response curve. Physicochemical properties and drug action A minor change in the chemical structure may cause dramatic change in activity and this is attributed to some physical factors CH 3 CH 3 CH 3 CH 3 N H3C N N N HO O OH HO O OH HO O OAc O AcO OAc Morphine Inactive 6-Acetylmorphine Heroin 4 2 The following physicochemical properties affect the pharmacokinetic profile of the drug. 1. Partition coefficient (log P) 2. Dissociation constant (PKa) 3. Steric factor 4. Solubility 5. Polymorphism Physicochemical properties of a drug affect drug action through their effect on ADME.  Routs of administration storage sites parentral rout site of action GIT Circulation Metabolism Excretion Parentral rout: IV, IA, intraspinal (No absorption barrier to reach blood) IM, SC, IP (Drug pass some membrane first) GIT route: where drug dissolution in GIT fluids, the dissolution rate depends on: a) Particle size: The smaller the particle size the larger the surface area the faster the dissolution (Spironolactone formulated in micronized form). b) pH of the medium: Weakly acidic drugs → dissolve in basic region in GIT, and vice versa Stomach pH (1- 3.5), duodenum (6 - 7), ileum (8)  Absorption Active transport or carrier mediated Passive diffusion Energy required No energy required Against conc. gradient According to conc. gradient similarity between the drug and the Not necessary natural substrate is needed Convective absorption: Small molecules (molecular radius < 4A° pass through water filled pores) and no energy required Passive diffusion Rate of diffusion is proportional to the drug conc, on the other side of the membrane -dC / dt : rate of diffusion dC - = K C1 d t C1 : concentration of drug at the site of absorption K : proportionality constant, depends on Rate of passive diffusion depends on: 1) area 2) thickness of the mambrane 3) partition coeffecient of drug a) Dissociation constant Most drugs are either weak acids or bases Henderson- Hasselbach Equation. Weak acids Weak base [ salt ] [ base ] pH = pKa + log pH = pKw - pKb + log [ acid ] [ salt ] b) Partition coefficient (log p) The logarithmic ratio between conc. of compound in organic phase to its conc. in aqueous phase at equilibrium CO log P = log CW e.g. barbital [pKa = 7.8, log P = 0.7] & secobarbital [pKa = 7.9, log P = 23.3] better absorption Sites of loss: 1- Protein binding 2- Metabolism 3- Excretion 4- Storage site Protein binding: drug-protein complex protein + free drug large complex inactive form active form Advantages 1. It is a storage site (release free drug slowly) 2. Contribute to long duration? (ME) Neutral fat: Partition into neutral fats depends on 1. Partition coefficient (log P) 2. Ionization const. (pKa) Excretion: For a drug to be excreted in urine it should be: 1. Suitable size (to pass glomerular membrane) 2. Soluble enough in aqueous medium at pH of urine 8 9 10 11 12 13 14 15 16 17 18 19 CH3COOCH2CH3 CH3COCH2CH3 RCOCH2CH3 RCOOCH2CH3 20 1 2 3 4 5 6 7