Transporter proteins toxicity and dosage can be

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Unformatted text preview: PhiP 2-amino-1-methyl-7-phenylimidazo(4,5)pyridine aromatic carcinogen Taxol used as chemotheraputeic ? Transporter Proteins • Toxicity and dosage can be largely dependant on these transporters •Cyclosporin and taxol toxicity is lower, great substrates for P-gp • PhiP (aromatic amine carcinogen) concentrations high in blood, high affinity for Mrp-2 (expression on baso-lateraland quickly taken away side) PhiP quickly pumped into blood chemotheraputic agents Substance LD50 (mg/kg) oral/IV cyclosporin 1480/ 148 taxol 34.8/ 2.3 10 fold toxicity difference from transporter protein effect alone! 2. Gastrointestinal Tract: “Oral Route” Factors Lowering Absorption a. Acid- hydrolysis or oxidation of compounds, degradation b. Enzymes (digestive & food)- can block transporters ie snake venom! c. Bacteria excess (dysbiosis) - 400 species in gut bacterial enzymes alter products - Metabolites (2,6-dinitrotoluene= activated) d. Increased peristalsis / movement (disease & stress) more movement, lower residency time lower absorption e. Diet- Grapefruit juice (inhibits specific transporter) NARINGIN = (P-gp) blocks P-gp protein - inhibits efflux, blood concentration higher blood concentration becomes toxic in blood, and doesn’t go where it’s supposed to f. Intra-luminal binding chelators: binding proteins, increase lipid solubility! ie EDTA 3. Respiratory System: “Pulmonary Route” Function: of lungs: 1. Clean & moisten air 2. Gas exchange 3. Acid/Base regulation through CO2 and carbonic cycle Tubular upper airway Lower Airways Gas exchange membrane 3. Respiratory System: “Pulmonary Route” Upper airways (tubular) conduct and condition air Protective mechanisms mucous, cilia (muco-ciliary ofpparatus) entire thing a layer mucs that layers - Physical barrier, traps particles, movement out of lungs - Compounds can have longer residency time Susceptible to corrosives i.e. acid pollution - Chemistry: add acid - Can dissolve in mucous, surface irritation of mucosa in RT nasoterminated: high surface area, high blood flow, and aq. surface responsible for heating air Nasal Turbinates (folds in nasal cavity) to sensitive - Thin layer o...
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