prodrug

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Prodrug Prodrug: • • • • Definition: A pharmacologically inactive compound that is converted to an drug by a metabolic biotransformation Prodrug-drug transformation could be enzymatic or nonenzymic Prodrug-drug conversion could occur before, during, after absorption or at a specific site in the body Ideally, conversion happens as soon as the target site is reached. 1 WWW.REVOLUTIONPHARMD.COM

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Reasons for Prodrug 1. 2. 3. 4. 5. 6. 7. 8. Solubility: some drugs are not soluble enough, attach a polar group to increase solubility, deliver it to the target, activated metabolically. Absorption and distribution: adjust the drug’s polarity and lipophilicity to escort it to the target Site specificity: in some cases, only certain organs can unmask a prodrug, use of these prodrugs can significantly enhance site specificity. Instability: modify a drug that may be rapidly metabolized Drug duration: add a handle on a drug so it is activated slowly Toxicity: a drug may be toxic, can be masked, delivered to target site and then unmasked Poor patient acceptibility: unpleasant taste or odor, produce gastric irritation or pain. It can be modified to avoid these undesired properties Formulation problems: e.g. a volatile liquid can be solidified for formulation as a tablet. 2 WWW.REVOLUTIONPHARMD.COM

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Definitions Carrier-linked prodrug: an active drug linked to a removable carrier (usually hydrolyzable group such as ester, amide, etc.) Bipartate prodrug: one carrier attached to one drug Tripartate prodrug: one carrier connected to a drug through a linker Mutual drug: two synergistic drugs attached to each other. Bioprecusor: A compound that is metabolized by molecular modification into a new compound that is the active principle or which can be metabolized further to the active drug Bipartate Tripartate Bioprecusor Carrier-linked prodrug linker biotransformation 3 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug A. Carrier linkages: alcohols and carboxylic acids esterases are ubiquitous degree of hydrophobicity and lipophilicity variable stability by adjusting electronic or steric effects . 4 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug B. Amines Amide not usually used because of high stability Activated amide or AA conjugates more readily hydrolyzed N-Mannich bases increase lipophilicity, variable hydrolysis rate Schiff base, increase lipophilicity H 2 N OH O NH 2 O Cl OH N F γ -aminobutyric acid Neurotransmitter unable to penetrate BBB Schiff base prodrug anticonvulsant Progabide able to penetrate BBB OH HN CH 3 NH O OH CH 3 NH 2 Phenylpropanolamine decongestant 1 Lipophilicity N-Mannich prodrug 100 5 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug C. Carbonyl Schiff base, acetals (ketals) increase lipophilicity Oxime increase hydrophilicity oxazolidines, thioxazolidines adjust lipophility. 6 WWW.REVOLUTIONPHARMD.COM

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R= R’=H, Prednisolone R= CH 3 , R’=H, Methylprednisolone Both are water-insoluble Ideal prodrug: shelf life > 2 yrs; activated < 10 min in vivo Prodrug: R=CH 3 , R’=COCH 2 CH 2 CO 2 Na shelf life<48hrs, others > 2 yrs R=H, R’=phosphate, good Carrier-linked prodrug 2. Examples of Carrier-linked Bipartate Prodrugs A. For Increased Water Solubility O H 2 N O Bezocaine Local anesthetic Low solubility H N O O H 3 N R O Bezocaine prodrug stable, long shelf life high solubility, activated readily 7 WWW.REVOLUTIONPHARMD.COM

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Bezodiazepine Tranquilizer diazepam Very low solubility Open-chain prodrug for Bezodiazepine Freely soluble in water Benzodiazepine alprazolam 0.015mg/ml Open-chain HCl salt, 109 mg/ml 8 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug 2. Examples of Carrier-linked Bipartate Prodrugs B. For Improved Absorption and Distribution Cortisosteroid Inflammation, Allergy Pruritic skin conditions Epinphrine, R = H Antiglaucoma 9 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug C. For Site Specificity H 2 N OH O 2. Examples of Carrier-linked Bipartate Prodrugs γ -aminobutyric acid Neurotransmitter Bacterial meningitis 300 times as potent as Vigabatrin unable to penetrate BBB Bodor et al. 1983. Pharmacol. Ther. 19 , 337 1987. Ann. N. Y. Acad. Sci. 507 , 289 Glycerol lipid (R=linolenoyl 10 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug 2. Examples of Carrier-linked Bipartate Prodrugs D. For Stability E. Prolonged Release Naltrexone(R=H), opiod addiction Not stable in the first pass R= CO- o -NO 2 Ph, bioavailability 45 times R= CO- o -AcOPh, bioavailability 28 times Tolmetin sodium(R=O - Na + ), antiarthritis Peak concentration duration: 1 hr. R= NHCH 2 COOH, peak duration: 9 hrs. 11 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug 2. Examples of Carrier-linked Bipartate Prodrugs F. To Minimize Toxicity G. To Encourage Patient Acceptance H. Elimination of Formulation Problems Aspirin: gastric irritation and bleeding When R=CH 2 CONR 1 R 2 , no problems Sulfa drug: pediatric antibiotics, bitter taste (R=H) When R=CH 3 CO, tastless Prodrug for formaldehyde: release HCHO in acidic condition Urine in bladder can be made acidic Used as urinary tract antiseptic 12 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug 3. Macromolecular Drug Carrier Systems etc. Target Cyclodextran Albumin Polyehtylene glycol Polylysine 1. 2. 3. 4. 5. 6. Protect drug until reaching target site Localize drug to target site Allow drug release Minimize host toxicity Biodegradable Stable enough. 13 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug 4. Tripartate Prodrugs General strategy Example: ampicillin 14 WWW.REVOLUTIONPHARMD.COM

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Carrier-linked prodrug 4. Mutual Prodrugs Two, usually synergistic, drugs attached to each other + Treat β -lactamase producing bacteria Pivampicillin Absorbed, transported to the same site 15 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor A compound that is metabolized by molecular modification into a new compound that is the active principle or which can be metabolized further to the active drug In vivo reactions that can activate a bioprecursor • • • • • Oxidative reaction Reductive activation Nucleotide activation Phosphorylation activation Decarboxylation activation 16 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor 1. Oxidative reaction: P450 enzymes A. N- and O-Dealkylations Bioprecursor prodrug for alprazolam and triazolam, the tranquilizers 17 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor 1. Oxidative reaction: P450 enzymes B. Oxidative Deamination Activation of cyclophosphamide: important cancer therapeutics Nitrogen mustard 18 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor 1. Oxidative reaction: P450 enzymes C. N-Oxidation Activation of procarbazine: cancer therapeutics against advanced Hodgkin’s disease ? 19 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor 2. Reductive Activation: A. Disulfide reduction Activation of Thiamin bioprecursor prodrug 20 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor 2. Reductive Activation: B. Bioreductive Alkylation Activation of anticancer antibiotic Mitomycin C 21 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor 3. Nucleotide activation 4. Phosphorylation activation Anticancer agent Acute childhood leukemias de novo DNA synthesis Incorporated into DNA after nucleotide formation Acyclovir, antiviral drug Genital herpes simplex virus & varicella zoster virus infection Incorporated into DNA as a G after Triple phosphorylation in infected cells Normal cells unaffected de novo DNA synthesis pathway Acyclovir (R=H) R=triphosphate, recognized as a dG by viral DNA polymerase but not recognized by normal cellular DNA polymerase dG 22 WWW.REVOLUTIONPHARMD.COM

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Bioprecursor 3. Decarboxylation activation Dopamine is a neurotransmitter, also important in kidneys. It increases systolic and pulse blood pressure and renal blood flow To increase renal blood flow but without blood pressure increase, it is desirable to deliver dopamine specifically to the kidneys Rich in the kidneys 23 WWW.REVOLUTIONPHARMD.COM

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Overview Carrier-linked prodrug: Bipartate prodrug Tripartate prodrug Mutual drug Bioprecusor: Oxidative reaction Reductive activation Nucleotide activation Phosphorylation activation Decarboxylation activation 24 WWW.REVOLUTIONPHARMD.COM

REFERENCES.:

REFERENCES. Moody TW, et al. Development of high affinity camptothecin-bombesin conjugates which have targeted cytotoxicity for bombesin receptor-containing tumor cells. J. Biol. Chem. 2004 , 279 , 23580–23589. 25 WWW.REVOLUTIONPHARMD.COM

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