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Dr. Phil Rowe Reader in Pharmaceutical Computing

Dr. Phil Rowe Reader in Pharmaceutical Computing. School of Pharmacy & Chemistry John Moores University Liverpool. Pharmacokinetics lecture 1 Contents . What is ‘Pharmacokinetics’ Absorption Distribution. Pharmacokinetics. “Drug movement” (Greek) The movement of drugs: Into Around

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Dr. Phil Rowe Reader in Pharmaceutical Computing

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  1. Dr. Phil RoweReader in Pharmaceutical Computing School of Pharmacy & Chemistry John Moores University Liverpool

  2. Pharmacokinetics lecture 1Contents ... • What is ‘Pharmacokinetics’ • Absorption • Distribution

  3. Pharmacokinetics “Drug movement” (Greek) The movement of drugs: • Into • Around • Back out of the body

  4. ADME • Absorption • Distribution • Metabolism • Excretion Elimination

  5. Absorption • Three mechanisms by which drugs may cross membranes: • Passive diffusion • Facilitated diffusion • Active transport • Passive diffusion MUCH more common than any of the others.

  6. Water Lipid Water Passive diffusion DRUG

  7. Requirements for passive diffusion • Water solubility • Lipid solubility • Almost all drugs are sufficiently water soluble to undergo passive diffusion, but some do lack the necessary lipid solubility. • In practice, passive diffusion depends mainly on lipid solubility.

  8. Efficiency of passive diffusion

  9. Water Lipid Water Facilitated diffusion DRUG Selective gateway allows entry of one group of molecules, but excludes all others.

  10. Water Lipid Water Active transport DRUG Structurally selective. Energy requiring Can operate against the concentration gradient

  11. Specificity • Passive diffusion • Non-specific. Anything lipid soluble • Facilitated diffusion • Active transport • Structurally specific groups of chemicals that fit a carrier molecule

  12. Specificity Few drugs handled by facilitated or active transport A molecule can only be handled by facilitated or active transport if the body contains a suitable carrier, so it is not surprising that very few drugs use such mechanisms. There are some examples. e.g. L-DOPA and gabapentin are transported into the brain by the Large neutral Amino Acid Transporter (LAT1)

  13. P-glycoproteins (Glycoproteins = proteins with carbohydrates attached) Gut contents P-gp in the apical cell membrane (facing the gut contents). Substances are absorbed, but then actively pumped back into the gut contents (Efflux). ATP dependent. Apical surface Intestinal epithelial cell Basolateral surface

  14. Location of P-glycoproteins OrganIntestineLiverKidneyBrain FunctionPrevent absorptionExcretion into bileExcretion into urinePrevent entry from blood into brain Generally a defensive mechanism against foreign substances

  15. Examples of substances where intestinal absorption is opposed by P-gp mediated efflux Celiprolol Beta blockerCyclosporin ImmunosuppressantDexamethasone GlucocorticoidIvermectin AnthelminticVerapamil AntihypertensiveVincristine Cytotoxic Wide range of drug groups and chemical structures

  16. Induction and inhibition of P-gp InductionExample - Rifampicin increase the amount of P-gp in the intestinal epithelium. Reduces absorption of other substances. InhibitionExample - Large enough dose of verapamil will saturate the P-gp. Other substances then absorbed more easily. Has been suggested as a means to increase absorption of problem molecules.

  17. Distribution Kidneys Fat Blood Etc. Liver

  18. Factors influencing distribution of a drug: • Ability to undergo passive diffusion (Already described) • Binding to macromolecules • Ion trapping • P-glycoproteins (Already described)

  19. Plasma protein binding Blood Cell Drug Drug Drug.Protein Lipid Total drug conc in blood greater than in cell.

  20. Intra-cellular binding Blood Cell Drug Drug Drug.Protein Lipid Nucleic acid Lipid Total drug conc in blood lower than in cell.

  21. Overall binding Blood Cell Drug Drug Drug.Protein Drug.Protein Lipid Nucleic acid Lipid Balance depends upon relative binding affinity in blood and tissues.

  22. R-NH2 R-NH2 + R-NH3 + R-NH3 Ion trapping Stomach (Acid) Blood (Neutral) Lipid Basic drugs accumulate in acidic environments. (Acidic drugs accumulate in basic environments.)

  23. Terms with which you should be familiar ... Pharmacokinetics ADME Absorption Passive diffusion Distribution Faciliated diffusion Metabolism Active transport Excretion P-glycoproteins Elimination Ion trapping

  24. What you should be able to do • Distinguish between metabolism and excretion • Describe the characteristics of passive diffusion, facilitated diffusion and active transport • Predict whether a given molecule will easily undergo passive diffusion • Describe the function of P-glycoproteins • Identify the factors that may influence the distribution of a given drug

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