This document discusses pharmacokinetics, membrane transport, and drug absorption. It describes how drugs pass through cell membranes via passive diffusion, filtration, or specialized transport mechanisms like carriers. Absorption of drugs can occur through the gastrointestinal tract, skin, or other routes and is influenced by properties like solubility and ionization. Bioavailability refers to the amount of drug that reaches systemic circulation after administration and is impacted by factors like first-pass metabolism. Together these concepts help explain how drugs are absorbed and distributed in the body.

1. PHARMACOKINETICS
MEMBRANE TRANSPORT AND
ABSORPTION
DR HARIKRISHNAN A R

2. Contents
Pharmacokinetics
Membrane transport
Absorption
Bioavailability

3. Pharmacokinetics
• Absorption, distribution, metabolism and elimination (ADME) of a drug
• Involves passage across numerous cell membranes
• Plasma membrane is the basic barrier
• Characteristics of drugs that predict the availability and movement are
1.Molecular size
2.Degree of ionisation
3.Relative lipid solubility
4.Its binding to serum and tissue proteins

4. Membrane transport
1. Passive diffusion and Filtration
2. Specialized transport

5. Passive diffusion
• Diffusion across membrane  concentration gradient
• Lipid soluble drugs  dissolves in lipoidal matrix
• Ionization of a weak acid
𝑝𝐻 = 𝑝𝐾𝑎 + 𝑙𝑜𝑔
𝑖𝑜𝑛𝑖𝑧𝑒𝑑
𝑢𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑
• Weakly acidic drugs  ionize at alkaline pH
• Weakly basic drugs  ionize at acidic pH
• Ions  lipid insoluble

6. Implications
• Acidic drugs  unionized in acidic gastric pH  well absorbed
• Basic drugs  ionized  absorbed at intestine
• Ion trapping  unionized form ionizes within the cell before passing
to ECF
• Basic drugs  higher conc intracellularly
• Lipid soluble non electrolytes  easily cross biological membranes

7. Filtration
• Aqueous pores in membrane
• Lipid insoluble drugs cross  molecular size smaller than pores
• Diffusion of drugs through capillaries  depend on rate of blood flow

9. Specialized transport
• Carrier transport  facilitated and active
• Vesicular transport  endocytosis and exocytosis

10. Carrier transport
• Carriers or transporters transport ions/solute across cell membrane
• Transporters combine transiently with their substrate
• Undergoes a conformational change  while carrying the substrate
• Substrate dissociates  transporter returns to normal state
• Carrier  specific for the substrate

11. Facilitated diffusion
• Transports substrate in the direction of electrochemical gradient
• No energy required
• Solute linked carrier(SLC) transporter
• E.g. GLUT 4  entry of glucose into muscle and fat cells

12. Active transport
• Transports solute against electrochemical gradient
• Requires energy
• Nonselective transporters like P-glycoprotein
Primary active transport
Secondary active transport

13. Primary active transport
• Energy  direct hydrolysis of ATP
• Transporters  ATP binding cassette (ABC)
• Mediate only efflux from cytoplasm to ECF or intracellular organelle
• Encoded by MDR1 gene
• P-glycoprotein  intestinal mucosa, renal tubules, bile canaliculi

15. Secondary active transport
• Energy  derived from downhill movement of another solute
• Symporter/co-transporter – in the same direction. Na+/K+/2Cl- symporter
• Antiporter/counter-transporter – in opposite direction. Na+-H+ exchanger

16. Vesicular transport
• Endocytosis  very large molecules transported into the cell
• Exocytosis  extruded from the cell
• Enclosing into tiny vesicles
• E.g. hormones, neurotransmitters

17. Absorption
• Movement of the drug from the site of administration to circulation
• Aqueous solubility
• Concentration
• Area of absorbing surface
• Vascularity of the absorbing surface
• Route of administration

18. Oral
• Non ionized lipid soluble drugs are absorbed
• Acidic drugs  stomach
• Basic drugs  duodenum
• Presence of food reduces absorption and delays gastric emptying
• Exceptions  fatty food increases absorption of lumefantrine

19. • Ineffective orally  degraded in GIT
• E.g. insulin by peptidases, penicillin G by acid
• Acid lability can be overcome by enteric coated or sustained release
tablets
• P-glycoprotein efflux in gut  digoxin, cyclosporin
• Interference by other drugs  luminal effect
• Eg tetracyclines and iron preparations with calcium salts
• Minimized by administering the drugs at 2-3 hr intervals

20. Subcutaneous and Intramuscular
• Drugs deposited near the capillaries
• Lipid soluble drugs
• Very large molecules are absorbed through lymphatics
• s.c. site is slower than that from i.m. site

21. Topical sites (skin, cornea, mucous
membranes)
• Lipid solubility
• Few drugs penetrate
• E.g. hyoscine, fentanyl, GTN
• Absorption promoted by occlusive dressing

22. Bioavailability
• Rate and extent of absorption from a dosage form administered by
any route
• Determined by concentration time curve in blood
• Measure of fraction of administered dose that reaches systemic
circulation
• Bioavailability of drug injected i.v.  100%
• Lower with oral route  incomplete absorption and first pass
metabolism

24. Bioequivalence
• Rate and extent of bioavailability of the active drug is not different
• Oral formulations from different manufacturers
• Differences in bioavailability  disintegration and dissolution rates

25. Measurement of bioavailability
• Absorption pattern of two brand products is plotted against time
• Peak plasma concentration{C max}
• Time to attain peak plasma concentration{t max}
• Area under the curve{AUC}
• C max and t max  indicators for the rate of absorption
• AUC extent of absorption
• C max, t max and AUC no significant difference  bioequivalent

27. 𝑫𝒓𝒖𝒈 𝒃𝒊𝒐𝒂𝒗𝒂𝒍𝒂𝒃𝒊𝒍𝒊𝒕𝒚(%) =
𝑨𝑼𝑪 𝒐𝒓𝒂𝒍
𝑨𝑼𝑪 𝑰𝑽
× 𝟏𝟎𝟎
NB: same dose is given orally and intravenously

28. Factors influencing absorption
and bioavailability

29. Pharmaceutical factors
• Particle size – surface area ↑ by ↓ particle size. e.g. micro-fined
aspirin, spironolactone
• Salt form – salt dissolves better. E.g. phenytoin sodium
• Crystal form – e.g. amorphous novobiocin have better bioavailability
• Water of hydration – E.g. anhydrous forms of ampicillin have better
bioavailability
• Nature of excipients and adjuvants – pharmacologically inert
substances (filling material or binding agent).
• Degree of ionisation – non ionised lipid soluble drugs are better
absorbed

30. Pharmacological factors
• Gastric emptying and gastrointestinal motility – gastric emptying ↑
absorption. Promoted by fasting, anxiety, lying on right side,
hypothyroidism and gastro-kinetic drugs
• Gastro-intestinal disease – in coeliac disease amoxicillin shows ↓
absorption while cephalexin shows ↑ absorption ampicillin shows no
change.
• Food and other substances – empty stomach ↑ absorption
• First-pass effect – drug degradation occurring before drug entering the
systemic circulation (oral drugs) therefore there is ↓ bioavailability

31. Cont.
• Drug-drug interactions – e.g. paraffin ↓ bioavailability of fat soluble
vitamins (emulsifies fats)
• Pharmacogenetic factors – e.g. slow acetylators of isoniazid show ↑
bioavailability in American whites  isoniazid toxicity
• Miscellaneous factors – route of administration, area of absorbing
surface, state of circulation at the site of absorption

32. Summary
• Pharmacokinetics
• Membrane transport and absorption
• Bioavailability

33. Thank you
Have a nice day