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Targeted Bioavailability : Mechanisms Influencing the Tissue Distribution of Drugs

Targeted Bioavailability : Mechanisms Influencing the Tissue Distribution of Drugs. June 8, 2005 The New England Drug Metabolism Discussion Group Summer Symposium University of Massachusetts Medical School Shrewsbury, Massachusetts. brain. William F. Elmquist, Pharm.D., Ph.D.

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Targeted Bioavailability : Mechanisms Influencing the Tissue Distribution of Drugs

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  1. Targeted Bioavailability : Mechanisms Influencing the Tissue Distribution of Drugs June 8, 2005 The New England Drug Metabolism Discussion Group Summer Symposium University of Massachusetts Medical School Shrewsbury, Massachusetts brain William F. Elmquist, Pharm.D., Ph.D. Department of Pharmaceutics University of Minnesota-Twin Cities

  2. Outline Background 1) Drug transport proteins in the body and the CNS drug disposition (overview) Experimental Studies 2) Delivery of Anti-tumor Agents (Gleevec) to CNS Summary 3) CNS drug delivery program and efflux transporters

  3. Why study drug transporters in the CNS barriers? Variability in Drug Response in the CNS - variability in distribution central - variability in receptors - variability in elimination and metabolism peripheral - variability in absorption

  4. Explain variability in drug response to PK and PD Bioavailability Definitions: FDA - “the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.” 21CFR320.1 Code of Federal Regulations, Title 21, Volume 5, Parts 300 to 499, 1999. ; Guidance for Industry, CDER, FDA, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations, 2003. Commonly accepted definition: Typically, one modifies this definition to limit the delivery path from the site of administration to the bloodstream, i.e., the term bioavailability is “the fraction of the oral dose that actually reaches the systemic circulation”, and “commonly applied to both the rate and extent of drug input into the systemic circulation”.

  5. Sources of Variability in Drug Response Variability Cycle Genetic Factors - drug targets - drug transporters - drug metabolizing enzymes Environmental Factors - induction - inhibition Physiological Factors - age, disease, etc.

  6. “Locations” of Variability in Drug Response Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Drug action Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  7. Physicochemical Properties Protein Binding Gene Regulation Drug Metabolism Protein Expression Receptor Affinity Dosage Regimen Physiology / Pathology Membrane Permeability Targeted Bioavailability Drug Transport Pharmacological / Toxicological Response

  8. Mechanisms influencing intestinal absorption: - solubility - permeability - transit time - carrier-mediated influx and efflux - stability - dosage form performance (disintegration, dissolution) “Locations” of Variability in Drug Response Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Drug action Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  9. “Locations” of Variability in Drug Response Oral dosage form Intestinal metabolism Tissue distribution Target site Mechanisms influencing the intestinal first-pass metabolism : - carrier-mediated transport - phase I metabolism (e.g., CYP3A4) - phase II metabolism (e.g., UGTs) - enzyme induction - enzyme inhibition - locations of windows of absorption - intestinal motility / transit time - genetic expression patterns Systemic circulation Drug action Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  10. Mechanisms influencing the intestinal first-pass metabolism : - carrier-mediated transport influx and efflux transporters - phase I (e.g., CYP3A4) - phase II (e.g., UGTs) - enzyme induction - enzyme inhibition - blood flow - protein binding - genetic expression patterns “Locations” of Variability in Drug Response Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Drug action Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  11. Mechanisms that influence the fraction of the drug in the systemic circulation that is available for distribution to target tissue and the exposure of the tissue to the drug - distribution of blood flow - ratio of total clearance to a distributional clearance Distributional clearance - membrane permeability, carrier-mediated transport (influx or efflux), protein-binding, intracellular metabolism, tissue transit time, capillary structure Total clearance – will affect the availability of the drug in the blood to distribute to the tissue “Locations” of Variability in Drug Response Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Drug action Intestinal absorption Liver metabolism Cellular delivery Systemic clearance Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  12. “Locations” of Variability in Drug Response Mechanisms that influence cellular delivery - membrane permeability - carrier-mediated transport (influx / efflux) - intracellular metabolism - receptor-mediated transport - binding Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Drug action Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  13. “Locations” of Variability in Drug Response Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Mechanisms influencing the drug action at the target site - intracellular signaling - intracellular transport - expression of target receptors - receptor affinity - availability of cofactors Drug action Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  14. “Locations” of Variability in Drug Response Examine a location Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Drug action Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  15. Examine a location considering the interplay between external factors and mechanism Physicochemical Properties External factors External factors Protein Binding Gene Regulation Drug Metabolism Protein Expression Mechanisms Receptor Affinity Dosage Regimen Membrane Permeability Targeted Bioavailability Physiology / Pathology Drug Transport Targeting modalities Pharmacological / Toxicological Response

  16. “Traditional Bioavailability” F = Fa x Fg x Fh 100 mg 30 mg 80 mg 60 mg Fh = 0.50 Fg = 0.75 Fa = 0.80 30 mg 20 mg 20 mg F = .80 x .75 x .5 = 0.3

  17. At each location, several mechanisms at play: Influence of fruit juices on oral bioavailability “traditional bioavailability”

  18. F = fa x fg x fh

  19. Complexity of the Transporter Problem at Various Barriers basolateral apical intracellular Carrier in Carrier in PSin Carrier out Bidirectional PSout Bidirectional PSout PSin Carrier out Many processes can be occurring simultaneously!

  20. “Targeted” BioavailabilityF = Fa x Fg x Fh and Fd , Fc , Ft Oral dosage form Intestinal metabolism Tissue distribution Target site Systemic circulation Drug action Fa Fg Fh Fd Fc Ft Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  21. Importance of Transporters in the Disposition of Drugs From Lee and Gottesmann. Journal of Clinical Investigation, 1998 illustration by Naba Bora, Medical College of Georgia.

  22. Adapted from Quentin Smith Compartmental model for solute exchange in the brain

  23. Transgenic mice Microdialysis Pardridge, 1998

  24. Blood-Brain Barrier (BBB) Basolateral membrane Apical membrane

  25. Cooray et al., 2002 NeuroReport microvessel from normal brain stained for GLUT-1 and BCRP GLUT-1 on both inner and outer walls of the microvessel BCRP shows a more narrow distribution

  26. Background Selected Drug transport systems in BBB and BCSFB Apical -- blood OATP2 MCT1 BCRP ? P-gp MRP1, MRP4, MRP5 MCT1 ? OATP2 BBB endothelial cell ? Basolateral -- brain MCT1-- monocarboxylate transporter OATP2-- organic anion transport protein 2 MRP -- multidrug resistant-associated protein (ABCCX) P-gp -- p-glycoprotein (ABCB1) BCRP – breast cancer resistance protein (ABCG2)

  27. Murakami, 2000 PS (in situ perf) versus logP(MW- ½)

  28. Influx Efflux

  29. Barriers to Drug Delivery Intestinal metabolism Tissue distribution Target site location of variability Oral dosage form Systemic circulation Drug action location of variability Intestinal absorption Liver metabolism Cellular delivery Presystemic bioavailability questions (“traditional” bioavailability) Site-specific bioavailability questions (drug targeting) Targeted Bioavailability

  30. Outline Background 1) Drug transport proteins in CNS drug disposition (overview) Experimental Studies 2) Delivery of Anti-tumor Agents to CNS Summary 3) CNS drug delivery program and efflux transporters

  31. CNS Delivery of Anti-tumor Agents 1) Brain Around Tumor - BAT (growing edge) 2) Membrane permeability vs. efflux transport 3) Tumor vasculature 4) Primary and secondary tumors (metastases)

  32. STI-571 (GleevecTM) CH3SO3H Recently approved for chronic myelogenous leukemia (CML) Several clinical trials currently underway for glioma

  33. Mechanism of Action of STI-571 “Molecularly Targeted” Therapy

  34. Kaplan-Meier survival plots intracerebral human glioma nude mice STI-571 txt bid PO 50 mg/kg/day Ras transformed negative control PDGF qd dosing Kilic, et al., Canc.Res., 2001 glioma

  35. Whole-body Autoradiography of Pigmented Rats From Novartis Pharma

  36. Methods • The directional flux of STI-571 was studied in MDCKII epithelial cell monolayers, using Transwell inserts. The effect of P-glycoprotein inhibition on the directional flux was also determined. • In vivo brain distribution studies were done using wild-type and mdr-1a/b (-/-) knockout mice. Mice were administered 25 mg/kg 14C-STI-571 orally, or STI-571 intravenously and brain-to-plasma concentration ratios of STI-571 were determined 30, 60 and 120 minutes post dose. RP-HPLC was used to determine the radioactivity associated with parent drug or LC-MS was used . mdr 1a/b (-/-) knockout mice wild type mice

  37. In Vitro Experiment

  38. STI-571 Flux MDR1-transfected MDCKII epithelium Corrected flux ratio 4.5-fold “Corrected” flux = (B-to-A / A-to-B)mdr (B-to-A / A-to-B)wt

  39. In VitroExperiment

  40. In Vitro Experiment

  41. Effect of Specific P-gp inhibition on STI-571 Flux

  42. RESULTS The directional flux of 14C-STI-571 was studied in MDCKII epithelial cell monolayers. MDR WT

  43. Gleevec Brain Distribution Brain/Plasma ratio KO = 11.2 fold opportunity for Brain/Plasma ratio WT targeted bioavailability

  44. Brain and Plasma Concentrations (LC-MS) A – Plasma STI-571 conc vs time B – Brain STI-571 conc vs. time C – increase in STI-571 brain penetration in the P-gp knockout enhanced: 6-8 fold ! “targeted bioavailability”

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