Lecture 7 PHARMACOKINETICS

Aspects of Drug Pharmacokinetics (ADME) Drug at site of administration Absorption Drug in plasma Distribution Drug/metabolites in tissues Metabolism Elimination Drug/metabolites in urine, feces, bile

Absorption

Absorption Definition : The process of movement of unchanged drug from the site of administration to systemic circulation. The ultimate goal is to have the drug reach the site of action in a concentration which produces a pharmacological effect. No matter how the drug is given (other than IV) it must pass through a number of biological membranes before it reaches the site of action.

LIPID BILAYER KLECOP, Nipani 08/10/2010

Factors Affecting GIT Absorption Blood Flow To Absorptive Site: Greater blood flow raises absorption Intestine has greater BF than stomach Total Surface Area of Absorptive Site: Intestinal microvilli increases surface area to 1000- fold that of the stomach favoring intestinal absorption Contact Time at Absorptive Site: Diarrhea reduces absorption Accelerated gastric emptying→ faster delivery to intestinal large surface → increased absorption

Factors Affecting GIT Absorption Food: Presence of food in the gut reduces/delays drug absorption from GIT Increased splanchnic blood flow during eating increases drug absorption Ionized drugs as tetracycline can form insoluble complexes with Ca2+ in food/milk. Formulation Factors: Solid dosage forms dissolution & solubility are essential Aqueous solutions are absorbed more quickly than tablets or suspensions

PHYSICOCHEMICAL FACTORS Drug transported by passive diffusion depend upon: dissociation constant, pKa of the drug pH at absorption site. lipid solubility, K o/w. Polarity estimates partition coefficient. The greater the lipid solubility – the faster the rate of diffusion Most drugs are either weak acids or weak bases whose degree of ionization is depend upon pH of biological fluid.

For a drug to be absorbed, it should be unionized and the unionized portion should be lipid soluble. Only non-ionized fraction of drugs (acids or bases is absorbed The fraction of drug remaining unionized is a function of both Dissociation constant (pKa) and pH of solution.

HENDERSON HASSELBATCH EQUATION For acid, pKa - pH = log[ Cu/Ci ] For base, pKa – pH = log[ Ci/Cu ] Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99%of unionized form so gets absorbed in stomach Weak base quinine (pKa=8.5) will have very negligible unionization in gastric pH so negligible absorption Several prodrugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds.

DIFFUSION THROUGH MEMBRANES Absorption facts: Smaller molecules penetrate more rapidly. The membrane is Highly permeable to O2, CO2, NO and H2O . Large polar molecules – sugar, amino acids, phosphorylated intermediates – poor permeability. These are essential for cell function, and thus must be actively transported

MOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES KLECOP, Niani

MECHANISMs OF DRUG ABSORPTION Passive diffusion Carrier- mediated transport a) Facilitated diffusion b) Active transport PINOCYTOSIS KLECOP, Nipani 08/10/2010

PASSIVE DIFFUSION Also known as non- ionic diffusion. It depends on the difference in the drug concentration on either side of the membrane. Absorption of 90% of drugs. The driving force for this process is the concentration or electrochemical gradient.

2) CARRIER MEDIATED TRANSPORT MECHANISM Involves a carrier (a component of the membrane) which binds reversibly with the solute molecules to be transported to yield the carrier solute complex which transverses across the membrane to the other side where it dissociates to yield the solute molecule The carrier then returns to its original site to accept a fresh molecule of solute. There are two types of carrier mediated transport system: a) facilitated diffusion b) active transport

a) Facilitated diffusion This mechanism driving force is concentration gradient. In this system, no use of energy is involved (down-hill transport), therefore the process is not inhibited by metabolic poisons that interfere with energy production.

b) Active transport More important process than facilitated diffusion. The driving force is against the concentration gradient or uphill transport. Since the process is uphill, energy is required in the work done by the barrier. As the process requires energy, it can be inhibited by metabolic poisons that interfere with energy production.

Drug Absorption Active vs. Passive Active transport: Carrier-mediated Energy-dependent Against conc gradient Shows carrier saturation kinetics Passive transport Energy-independent No carrier involved Along conc gradient No saturation kinetics ATP Carrier-mediated energy-dependent active transport ADP + Pi Passive diffusion of a water-sol drug via aqueous channel AH B Passive diffusion of a lipid-sol drug A- BH+

3) Pinocytosis This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.

Bioavailability the proportion of the drug in a dosage form available to the body Fraction of a drug reaching systemic circulation in chemically unchanged form after a particular route First pass metabolism, i.e., rapid hepatic metabolism, reduces bioav. (lidocaine, propranolol, nitrates)

BIOAVAILABIITY Time Injected Dose Serum Concentration Oral Dose Drug solubility Chemical instability in gastric pH (penicillin G, insulin) Drug formulation: Standard & SR formulations Bio = AUC oral/AUC IV x 100 Injected Dose Serum Concentration Oral Dose Time

Therapeutic success of a rapidly & completely absorbed drug. Not only the magnitude of drug that comes into the systemic circulation but also the rate at which it is absorbed is important this is clear from the figure. Plasma Drug Conc. Minimum effective conc. Therapeutic failure of a slowly absorbed drug. Subtherapeutic level Time