CHAPTER 7 ABSORPTION KINETICS 1 ABSORPTION GIT 2

CHAPTER 7 ABSORPTION KINETICS 1

ABSORPTION GIT 2

ABSORPTION FROM GIT Oral Dosage Forms 3

Advantages of Oral Drugs v Convenient, portable, no pain v Easy to take v Cheap, no need for sterilization v Compact, multi-dose bottles v Automated machines producing tablets in large quantities v Variety- fast release, enteric coated, capsules, slow release, …. . 4

ABSORPTION Definition: is the net transfer of drug from the site of absorption into the circulating fluids of the body. For Oral Absorption 1 - Cross the epithelium of the GIT and entering the blood via capillaries 2 - Passing through the hepatoportal system intact into the systemic circulation 5

ABSORPTION 6

Biological Membranes No matter by which route a drug is administered it must pass through several to many biological membranes during the process of absorption, distribution, biotransformation and elimination. 7

Cell Membrane Structure It is a bimolecular layer of lipid material entrained between two parallel monomolecular layers of proteins. 8

Cell Membrane Structure The cell membrane appears to be perforated by water-filled pores of various sizes, varying from about 4 to 10 A 9

Drug Transport is the movement of drug from one place to another within the body. Most drugs pass through membranes by diffusion. The process is passive because no external energy is expended. PARACELLULAR TRANSCELLULAR 10

PASSIVE DIFFUSION The passage of drug molecules occurring from the side of high drug concentration to low drug concentration 11

Fick’s law of diffusion Q: is the net quantity of drug transferred across the membrane, t: is the time Ch: is the conc on one side (GIT) and Cl: that on the other side (plasma) x: is the thickness of the membrane A: is surface area of membrane and D: is the diffusion coefficient related to permeability k: is the partition coefficient of the drug 12

SMALL INTESTINE VILLI 13

PERMEABILITY The permeability of a membrane to a drug depends on physico-chemical properties of drugs: Lipophilicity: membranes are highly permeable to lipid soluble drugs Molecular size: important in paracellular route and in drugs bound to plasma protein. Macromolecules such as proteins do not traverse cell membrane or do so very poorly Charge: cell membranes are more permeable to unionized forms of drugs because of more lipid solubility 14

PERMEABILITY 15

Carrier-Mediated Transport Active Transport The drug is transported against a concentration gradient. This system is an ENERGY consuming system. Example: Glucose and Amino acids transport. 16

Passive Facilitated Diffusion A drug carrier is Required but no ENERGY is necessary. e. g. vitamin B 12 transport. Drug moves along conc gradient (from high to low), downhill but faster DRUG CARRIER 17

DRUG TRANSPORT 18

Characteristics of GIT 19

Effect of Food on Drug Absorption Propranolol 20

Effect of Diseases on Drug Absorption Diseases that cause changes in: Ø Intestinal blood flow Ø GI motility Ø Stomach emptying time Ø Gastric and intestinal p. H Ø Permeability of the gut wall Ø Bile and digestive enzyme secretion Ø Alteration of normal GI flora 21

Simulation of Drug Absorption by Dissolution Methods Dissolution tests in vitro measure the rate and extent of dissolution of the drug from a dosage form in an aqueous medium 22

ABSORPTION KINETICS Plasma Concentration-Time Curve Cmax Cp Absorption Elimination Phase Tmax Time 23

First-Order Absorption 24

Absorption Zero-Order Absorption: is seen with controlled release dosage forms as well as with poorly soluble drugs. The rate of input is constant. First-Order Absorption: is seen with the majority of extravascular administration (oral, IM, SC, rectal, ect. . ) Most PK models assume first-order absorption unless otherwise stated. 25

One Compartment Model for First-Order Absorption and First-Order Elimination Gastrointestinal, Percutaneous, Subcutaneous, Intramuscular, Ocular, Nasal, Pulmonary, Sublingual, … Drug in dosage form Release Drug particles In body fluid Dissolution Drug in solution Central Compartment Absorption (Plasma) ka kel Elimination 26

COMPARTMENTAL MODEL One compartment model with Extravascular administration Drug in GIT ka Central Compartment kel Route of Administration: Oral, IM, SC, Rectal, ect… 27

First-Order Absorption Model Rate of change = rate of input – rate of output Integrated Equation: 28

The Residual Method The rising phase is not log-linear because absorption and elimination are occurring simultaneously 29

The Residual Method 30

The Residual Method 31

The Residual Method 32

Cmax and tmax The time needed to reach Cmax is tmax At the Cmax the rate of drug absorbed is equal to the rate of drug eliminated 33

Lag Time The time delay prior to the commencement of first-order drug absorption is known as lag time Cp Lag time Time 34

FLIP-FLOP of ka and kel In a few cases, the kel obtained from oral absorption data does not agree with that obtained after i. v. bolus injection. For example, the kel calculated after i. v. bolus injection of a drug was 1. 72 hr -1, whereas the kel calculated after oral administration was 0. 7 hr -1. When ka was obtained by the method of residuals, the rather surprising result was that the ka was 1. 72 hr -1 35

FLIP-FLOP of ka and kel ØDrugs observed to have flip-flop characteristics are drugs with fast elimination (kel > ka) ØThe chance for flip-flop of ka and kel is greater for drugs that have a kel > 0. 69 hr-1 ØThe flip-flop problem also often arises when evaluating controlled-release products ØThe only way to be certain of the estimates is to compare the kel calculated after oral administration with the kel from intravenous 36 data.

FLIP-FLOP of ka and kel 37

Effect of size of the dose of a drug on the peak concentration and time of peak concentration The time of peak conc is the same for all doses A >B >C 38

Effect of altering ka on Cmax and Tmax The faster the absorption the higher is the Cmax and the shorter is the Tmax 39

Effect of altering kel on Cmax and Tmax The faster the elimination the lower is the Cmax and the shorter is the Tmax ka= 0. 5 hr-1 kel= 0. 02 hr-1 ka= 0. 5 hr-1 kel= 0. 2 hr-1 Cp ka= 0. 5 hr-1 kel= 20 hr-1 Time 40

Equations 41