Bioprecursor Prodrugs

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Presentation transcript:

Bioprecursor Prodrugs Reduction example - Mitomycin C - Mutamycin® - Bristol Myers Adenocarcinoma of the stomach and pancreas

Bioprecursor Prodrugs Phosphorylation example –

Chemical Delivery Systems We have already seen 2 examples of this: Sulfasalazine – an azo compound Methenamine – An urinary antibacterial agent Requirements Prodrug reach the site of action in high concentrations Knowledge of high metabolism at site Other factors Extent of organ or site perfusion Information on the rate of prodrug conversion to the active form at both target and non-target sites Rate of input/output of prodrug from the target site Limit side effects and increase effectiveness

Chemical Delivery Systems Types of carriers that have been used Proteins Polysaccharides Liposomes Emulsions Cellular carriers (erythrocytes and leukocytes) Magnetic control targeting Implanted mechanical pumps What is the Basic Goal? Protect a non-specific biological environment from a drug Protect a drug from a non-specific biological environment Especially evaluated for drugs with a narrow therapeutic window especially anti-cancer agents

Chemical Delivery Systems The ideal situation: Prodrug readily transported to the site of action Prodrug is rapidly absorbed at the site Selective and rapid conversion to the active drug Kidney and Liver are easy targets due to high perfusion and high metabolic rates Other tissue sites can be problematic for the same reasons Drug migrate slowly (site of action to a site of excretion) Ideal situation is VERY complex to achieve Example: Methenamine the lower the pH, the faster the rate of formaldehyde formed blood pH 7.4 therefore, little formaldehyde formed

Chemical Delivery Systems Example: Cancer Chemotherapy Tumor cells have a much higher growth fraction This translates into higher enzymatic activity that can be exploited Target a prodrug to these sites and exploit higher enzyme activity Example: L-Dopa or Levodopa – Anti-Parkinsonism agent Larodopa® – Roche and Dopar® - Procter & Gamble Brain has a specific transport system for L-amino acids Dopamine does not cross the blood brain barrier efficiently, is rapidly metabolized by oxidative deamination, and can cause peripheral side effects