Presenter : VISHNU SRAVAN.B M.pharmacy pharmacology IInd semester SRR College of Pharmaceutical Sciences Overview 1. Introduction 2. Prodrug design 3. Applications 4. Conclusion 5. Reference www.pharmawiki.in Introduction www.pharmawiki.in What is a Prodrug ? Why Prodrug design ? Pharmacologically inactive compound which is metabolized to the active drug by either a chemical are enzymatic process. To decrease unpredictable interactions To increase therapeutic efficacy To decrease undesirable toxicity. Prodrug design www.pharmawiki.in Barrier To drug’s usefulness Drug Drug Chemical Modification Pro Drug Barrier To drug’s usefulness Pro Drug Biotransformation Drug Excretion Barrier To drug’s www.pharmawiki.in Pharmaceutical phase Drug Pharmacokinetic phase Manufacture Release Dosage form Drug in sol. at admin site Elimination Absorption Drug in various body compartments Distribution Drug in blood Elimination Transport Pharmacodynamic phase Elimination Drug in target organ Rational Prodrug design www.pharmawiki.in 1. Identification of drug delivery problem. 2. Identification of physicochemical properties required for maximum efficacy or delivery. 3. Selection of transport moiety providing a Prodrug derivative exhibiting the proper physicochemical characteristic's and which can be cleaved in the desired biological compartment. Factors to be considered for designing Prodrug www.pharmawiki.in Purpose Expected properties Site of transformation Mechanism of transformation Chemical half life Solubility Prodrug linkage and Enzymes involved in hydrolyzing the link www.pharmawiki.in Prodrug Linkage Hydrolyzing Enzyme 1. Ester Short medium chain Cholinesterase Aliphatic Ester hydrolase , Lipase , Cholesterol Esterase, Acetyl cholinesterase , Aldehyde oxidase, Carboxypeptidase 2. Long chain aliphatic carbonate Pancreatic lipase,Pancreatin,Lipase, Carboxypeptidase, Cholinesterase 3. Phosphate, Organic Acid phosphatase, Phosphatase 4. Sulfate, organic Steroid sulfatase Alkaline Conti.. www.pharmawiki.in Prodrug Linkage Hydrolyzing Enzyme 5. Amide Amidase 6. Amino acid Proteolytic enzymes, Trypsin, Carboxypeptidase A and B, 7. Azo Azo reductase 8. Carbamate Carbamidase 9. Phosphamide Phosphoramidases 10. β-Glucuronide β-Glucuronidase Applications www.pharmawiki.in 1. Towards pharmaceutical problems 2. Towards pharmacological problems 3. Site specific drug delivery 4. Sustaining drug action www.pharmawiki.in 1.Patient acceptability : a. •Has bitter taste •Unsuitable for suspension preparation •Taste less /inactive cinnamate or esters forms b. • Antimicrobial metranidazole • Bitter taste • Suspension of Benzoyl metranidazole (Flagel S) www.pharmawiki.in 2. Drug solubility: a. Anti inflammatory corticosteroids in the form of disodium phosphate or sodium hemisuccinate. Phosphate esters of steroidal anti-inflammatory agents Hemisuccinate salts steroidal anti-inflammatory agents b. Water soluble derivative of phenytoin , Metabolized in vivo by phosphatase Phosphatases More readily available ACTIVE DRUG Esterase Less readily Available www.pharmawiki.in 3. Drug stability: The breakdown on prolonged storage. To prevent Rapid degradation on oral administration b. a. Erythromycin estolate (lauryl sulfate salt of propionyl ester) CO2H NHSO2 N N N Colon bacteria Esterase's Sulfapyridine NHSO2 OH NH2 N Erythromycin Sulfasalazine - Azulfidine® - Pharmacia & Upjohn Sulfonamide antibiotic and antiinflammatory Used to treat Ulcerative colitis, rheumatoid arthritis + CO2H H2N OH 5-aminosalicylic acid www.pharmawiki.in 1. Drug absorption: Variation in efficacy between patients, due to unpredictable side drug absorption from G.I.T . Bioavailability of many drug compounds can be optimized by Prodrug concept. Examples: b. a. www.pharmawiki.in c. d. www.pharmawiki.in e. Soft quaternary salts 1. Improved bioavailability of pilocapine on ocular administration. Mechanism 2. Treatment Glaucoma with Adrenaline. 2. Drug distribution: www.pharmawiki.in The modification of a drug to a pro-drug may lead to enhanced efficacy for the drug by differential distribution of the pro-drug in body tissues before the release of the active form. Examples: 1. Hetacillin( methoxy methyl ester) Ampicillin (More tissue distributed) 2. Cyclophosphamide does not possess alkylating properties and consequently is not a tissue vesicant Conti.. www.pharmawiki.in www.pharmawiki.in Pro-drugs have more recently been used to achieve site-specific drug delivery to various tissues. Such pro-drugs are designed to ensure that the release of the active drug only occurs at its site of action thereby reducing toxic side-effects due to high plasma concentrations of the drug or non-specific uptake by other body tissues. 1. Dihydropyridine—pyridinium salt type redox system : Nerve gas antagonist pralidoxine into the CNS . 2. Spirothiazolidine derivative of hydrocortisone shows better Anti-inflammatory activity applied Topically and its Systemic effect was decreased after absorption. www.pharmawiki.in 3. Site specific delivery in solid tumors can be achieved by generating hypoxic environment 4. p-nitro substituent of β- chloroethylamine Normal environment Formation of alkylating carbonium ion is prevented. Hypoxic environment Alkylating species is formed. www.pharmawiki.in 5. ADEPT (Anti body directed enzyme Prodrug therapy) . Antitumor antibody conjugated to an enzyme. The conjugate is localized at the tumour site via an antibody-antigen interaction and converts a subsequently administered pro-drug into a cytotoxic Taxol ADEPT β-lactamase enzyme antitumor antibody Conjugate. pro-drug (PROTAX) = taxol + cepham sulphoxide agent which attacks the tumour. www.pharmawiki.in Pro-drug design has also been successfully used to modify the duration of action of the parent drug by either reducing the clearance of the drug or by providing a depot of the parent drug. Drug Prodrug Action Adrenaline Bitolterol Bronchodilator Phenothiazines Flupenthioxol Antipsychotic Vasopressin Glypressin Against Esophageal varicose www.pharmawiki.in Conclusion Recent advances in biotechnology have made it possible to utilize pro-drug design to develop chemical drug delivery systems which provide various means of targeting the delivery of parent drugs to specific sites within the body. Clearly, the increasing demands for more efficacious and less toxic drugs will ensure that Prodrug approaches continue to be exploited in the development of future drug substances. www.pharmawiki.in References 1. 2. Smith and Williams Introduction to the Principles of Drug Design and Action Third edition Edited by H. John Smith Welsh School of Pharmacy University of Wales Cardiff, UK . Amsteldijk 166 1st Floor1079 LH Amsterdam The Netherlands. Povl Krogsgaard-Larsen, Tommy Liljefors and Ulf Madsen Textbook of Drug Design and Discovery Third edition First published 2002 by Taylor & Francis 11 New Fetter Lane, London EC4P 4EE.