Pharmacokinetics Lecture 1 Overview PDF

URNALS $$ BOOKS ABOUT $$ AUTHOR GUIDE $$ SUBMIT Pharmacokinetics nternational LectureJournal of I: Overview...

URNALS $$ BOOKS ABOUT $$ AUTHOR GUIDE $$ SUBMIT Pharmacokinetics nternational LectureJournal of I: Overview harmacokinetics Submi What does our body do SN (print ): 2053-0846 | ISSN (online): 2053-0854 to the drug? quency: 4 issues per y ear eToC ernational Journal o f Pharmacokinetics w elcomes unsolicited article oposals. Email us today to discuss the suitabilit y of your research and our ions for authors, including our Accelerated Publication and Open Access Pr vices. spe low us on social media f or the latest updates Dr Miriam Moriarty https://www.future-science.com/toc/ipk/current [email protected]  Lecture I. Learning Objectives At the end of the lecture, you should be able to answer the following questions: ❖ What is pharmacokinetics? ❖ What is absorption and how does it affect the route of administration? ❖ What is distribution? ❖ What is metabolism? ❖ What is elimination?  Recommended reading (for this set of 8 Pharmacokinetics lectures) 1. Rang H.P., et al., (2020). Pharmacology. 9th Edn. Elsevier. Chapters 9,10 and 11 for 9th edition 2. Golan, DE et al., (2017) Principles of Pharmacology 4th edn. LWW. Chapter 1 3. Harvey, et al., (2015): Lippincott’s Illustrated Reviews Pharmacology, 6th Edition. Lippincott, Williams & Wilkins Chapter 3 and 4  Pharmacokinetics ❖ defined as the study of the fate of a drug over time through the body ❖ studies the absorption, distribution, metabolism, elimination (ADME) of the drug and bioavailability. = what the body does to the drug A drug’s pharmacokinetic properties enable to determine: the routes by which a drug can be administered the frequency of drug administration to achieve therapeutic concentrations the extent that the drug penetrates into the body’s compartments prediction of the plasma concentration at a selected time following administration the rate of clearance out of the body the routes of elimination the impact of administration of other drugs on these properties  Example 1 Patrick has back pain, and he is taking ibuprofen. Pharmacokinetics will answer these questions: - How long does it take for the drug to act? - How long will the drug have an effect? - When should Patrick take another tablet? - Will a cream be as much effective as an oral tablet?  The principles of ADME ❖ Absorption Needs an adequate ❖ Distribution concentration in the target tissue ❖ Metabolism ❖ Elimination/Excretion  Compartmental modeling of pharmacokinetics describes the fate of a drug in the body by dividing the whole body into one or more compartments. URINE https://quizlet.com/373148856/pharmacokinetics-2-compartment-modelling-flash-cards/  Absorption the drug from the site of administration has to get into the bloodstream -routes of administration -barriers to cross (what and how (pH, size, charge?) Routes of administration ?  Routes of administration Enteral Routes (GIT related) Parenteral Routes (not related to GIT) - Oral (mouth-swallow) - IV (intravenous injection) - Sublingual (under the tongue) - IM (injection into the muscle) - Rectal (suppositories) - SC (subcutaneous injection under the skin) Systemic Local - Intrathecal (injection into the cerebrospinal fluid) - Topical (skin, eyes) - Transdermal - Intranasal (nasal drops) - Inhalation into lungs DOI: 10.3390/polym14051010  Absorption No absorption is required if the: -drug is given for local effect – topical (skin, eye) -drug injected into bloodstream – IV injection  Distribution from the blood to the tissue from blood to the tissue Except if no absorption is required: topicals, iv administration  Distribution The drug must cross barriers- DIFFUSION depends on the characteristics of the drug: lipid solubility, polarity, size, charged/uncharged Cross GIT epithelium Get into the bloodstream (absorption) Cross endothelium Get from blood to tissue (distribution)  Metabolism converts non-polar drugs into polar metabolites Phase I - convert lipophilic drugs into more polar molecules by adding or exposing a polar functional group: reduction, oxidation, or hydrolysis reactions. Phase II - reactions conjugate (add on) polar substituents onto the drug to make it more polar and water-soluble. https://www.semanticscholar.org/paper/DRUG-METABOLISM-IN-THE-LIVER-Nguyen  Elimination/Excretion the removal of drugs from the body, either as a metabolite or unchanged drug Kidneys!!! (non-volatile, water-soluble) Gut!! Others: lung (volatile), skin sweat, tears, saliva, milk, hair  Summary make non-polar to metabolism polar for kidney excretion non-polar has to dissolve in lipid Pharmacokinetic parameters  Pharmacokinetics parameters Half-life (T1/2): the time taken for the drug plasma concentration to fall by half, measured in minutes/hours Elimination rate constant (Kel): the fraction of drug eliminated per unit time, i.e. the rate at which the drug is removed from the plasma, measured in h-1 Clearance (Cl): the volume of plasma from which a drug is completely eliminated per unit time, measured in mL or L.h-1 Volume of distribution (Vd): This is a theoretical volume in which a drug resides, if it was distributed to the same extent throughout the body as that encountered in the plasma, measured in L Pharmacokinetic drug profile for fluoxetine Oral Bioavailability: 85%1 Metabolism: Fluoxetine is Metabolic pathway5: metabolized primarily via N- Time to Cmax: 6-8 hours2 demethylation to the active metabolite norfluoxetine4 Volume of distribution: 20 to 3 drug interactions Elimination: 42 L/kg (i.e. 1400-2940 L in a 70 1. When fluoxetine is coadministered with Half life: 1-3 days after acute tricyclic antidepressants (TCAs), there is a 2 kg person, i.e. a very large Vd)3 to 4 fold increase in plasma TCA administration, and 4-6 days Plasma Protein binding: 94%, concentrations with signs of toxicity4 after chronic administration. i.e. extensively protein bound 2. Coadministration of fluoxetine with the The elimination half life of References: antipsychotic risperidone is associated with a 75% elevation in plasma norfluoxetine, ranges from 4-16 1http://www.inchem.org/documents/pims /pharm/pim651.htm#SectionTitle:5.1%20 concentrations of the active fraction days3 %20Oral of risperidone4 Excretion: Primarily eliminated 2https://www.accessdata.fda.gov/drugsatf 3. Fluoxetine and warfarin may be associated with enhanced anticoagulant in the urine3 da_docs/label/2006/018936s076lbl.pdf 3https://go.drugbank.com/drugs/DB00472 activity probably due to fluoxetine 4file:///C:/Users/0001204s/Downloads/clin inhibiting the CYP2C9-mediated Clearance: 0.6 L/h/kg3 ther-2008.pdf metabolism of the active S-enantiomer of warfarin4 5https://www.mdpi.com/1420- Example 3049/26/7/1917/htm# from Prof J Kelly  Pharmacokinetics parameters Tell the drug developer: ❖ how the drug is absorbed after administration, the routes it can be administered ❖ how the body distributes the drug into different bodily compartments or tissues ❖ how the body metabolizes or degrades the drug ❖ how the body excretes the drug ❖ predict plasma concentration at a selected time following administration ❖ the impact of concomitant administration of other drugs on these parameters Questions?