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Pharmacokinetics (PK): What the body does to the drug?

Pharmacokinetics (PK): What the body does to the drug?. Most drugs: Enter the body by crossing barriers Distributed by the blood to the site of action Biotransform perhaps to several different compounds by enzymes evolved to cope with natural materials Excreted

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Pharmacokinetics (PK): What the body does to the drug?

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  1. Pharmacokinetics (PK):What the body does to the drug? Most drugs: • Enter the body by crossing barriers • Distributed by the blood to the site of action • Biotransform • perhaps to several different compounds by enzymes evolved to cope with natural materials • Excreted • which removes them and/or their metabolites from the body

  2. Pharmacokinetic Profile of a Plasma Concentration-Time Curve

  3. Why are Pharmacokinetics Important? If a drug is going to work, it needs to be: in the right place at the right concentration for the right amount of time Pharmacokinetics tells us: what dose to give how often to give it how to change the dose about drug interactions -

  4. Absorption • How does the drug get into the bloodstream? • How long does it take? • Routes of administration • IV • no absorption limitations • drug directly into venous blood • Oral agent • must be soluble • pass across membrane out of stomach or intestines • bioavailability concerns • Many other routes • Affects on drug absorption • gastric pH • food

  5. Distribution • How the drug travels in the bloodstream? • Movement of drug throughout the body • Areas of the body are specially protected from chemicals (including drugs) • Brain • Reproductive organs • Determine what percentage of the drug in the blood is stuck to proteins (called protein binding) • Only drug that is free of proteins can travel in and out of other areas of the body to be effective

  6. Metabolism • Biotransformation: How the body chemically changes a drug? • Mostly in the liver and GI tract • Break a drug down or add a chemical that makes it easier to pass it into urine or stool • Drug-drug interactions happen because one drug interferes with the metabolism of another drug (called inhibition). Inhibition causes higher drug levels. • Drug can also speed up the metabolism of another drug (called induction). Induction causes lower drug levels. • Factors that affect metabolism

  7. Cytochrome P450 (CYP 450) • Enzymes that change many drugs into a less toxic form that can be excreted by the body • Drug metabolism via the CYP 450 system has emerged as an important determinant in: • Occurrence of drug-drug interactions • Reduced pharmacologic effect of drugs • adverse drug reactions. • Most up-to-date information is from the Division of Clinical Pharmacology at Indiana University • http://medicine.iupui.edu/clinpharm/ddis/

  8. Elimination • How the body gets the drug and/or drug metabolites out of the body? • Primarily occurs in kidney with drug being excreted in urine • Also occurs in liver (elimination into bile  feces)

  9. Drug Disposition (ADME) Oral IV A M E M D E GI Tract Drug Blood Liver Kidney Tissue

  10. How do we learn about the pharmacokinetics of a drug? • In vitro • Experiments can provide information on: • Enzymes responsible for metabolism • Solubility • Preclinical studies • In at least two animal species (one non-rodent) • Experiments can provide information on: • Absorption, Distribution, Metabolism, Excretion • Clinical studies • Phase I studies and beyond

  11. Blood sampling… • PK samples are drawn in order to determine circulating concentrations of drug in the blood • Blood samples are drawn from the patient at varying intervals • Timepoints are normally designed based on the drug to ensure the best data without unnecessary bleeding of the patient

  12. …Blood sampling • Blood for PKs CANNOT be drawn from the same line delivering the drug • Samples drawn from the incorrect location are often useless • Can also measure drug levels in urine, feces, CSF

  13. Protocol and PKs • Protocol should contain information related to PKs • What tube(s) should be used? • When will samples be collected? • How long after collection do samples need to be processed? • What to do with samples in interim? • How are samples processed? • Speed and duration of time • Temperature • # of aliquots • How are samples stored? • Freezer temp • How/when are samples to be shipped? • PK worksheets

  14. Goal: Concentration-time profile Concentration (ng/mL) Concentration (ug/mL) “Typical” IV Drug “Typical” Oral Drug

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