Prodrugs kinetics

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CONTENTS Introduction Kinetic studies Biotransformation Pathway Enzymatic Models Analytical Models Types of prodrugs Synthesis Pharmaceutical applications Pharmacokinetic applications Conclusion References


INTRODUCTION A prodrug is a drug conjugate with improved properties. Paracetamol was the 1 st drug actively investigated for prodrug drug formation. Prodrugs for paracetamol were synthesized & investigated to reduce hepatic toxicity & increase its bioavailability. The recent innovations in the prodrugs are for controlled & sustained release of active drugs either at site of absorption/at site of the target.


KINETIC STUDIES Kinetics of release & degradation of a prodrug is an important consideration in prodrug design. helps in very stable & freelance kind of design of prodrugs. Half life of the prodrug & its solution / enzymatic degradation are the important factors in the evaluation of pharmacologically action of the prodrug. Stability studies with prodrugs can be simply divided into 3 methods. Biotransformation pathway identification, Enzymatic studies, Analytical methods.

Biotransformation Pathway Identification:

Biotransformation Pathway Identification It is the main initial investigation for prodrugs design. Its aim was to develop prodrugs that are more lipo-hilic than their parent drugs-cross cell membrane. Salient features for the design of prodrugs include : Should be more lipophilic than their parent drugs Should be stable in the strongly acidic medium of the stomach Should stay intact before being absorbed and reaching the target cells Should release the parent active drug by enzymatic mechanism

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As a first step, chemical stability of prodrugs was investigated. Expected hydrolysis products were determined with the help of CE/UV analyses. Then biological stability was determined in fetal calf serum, simulated gastric acid, and rate liver homogenate. In the next step, hydrolysis in fetal calf serum was determined.

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Finally, metabolism in liver enzymes was investigated. This shows significant degradation into parent compound in the presence of metabolic enzymes. If the target was brain, prodrug travels across the BBB and gets degraded into the active drug in the brain homogenates. Thus final result is identification of biotransformation pathway from intestines to the brain to its activity

Enzymatic Models :

Enzymatic Models Enzyme models are very essential in the investigations of pathway determinations of a prodrug. These models include 1.Tissue lysates 2.Cell Cultures 3.Hepatocyte Suspensions 4.Subcellular Fractions 5.Pure Enzymes 6.Microbial Cultures

Analytical Methods:

Analytical Methods Analytical methods useful in prodrugs studies include 1.UV-spectophotometry 2.HPLC 3.HP-TLC and 4.Capillary electrophoresis etc. These techniques are used in studying the biotransformation reactions, their kinetics and other miscellaneous investigations, as related to prodrug design and development.


TYPES OF PRODRUGS A variety of prodrugs are investigated Carrier linked prodrugs Bioprecursor prodrugs Site-specific chemical delivery systems Macromolecular prodrugs Drug-antibody conjugates Oxidation activated prodrugs Reduction activated prodrugs Hydrolysis activated prodrugs

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An ideal prodrug should possess following It should not have intrinsic pharmacological activity. It should rapidly transform, chemically, enzymatically, into the active form where desired. The metabolic fragments, apart from the active drug, should be nontoxic .


SYNTHESIS Soluble prodrugs for Parenteral use : These are synthesized as a first step to develop a parenteral formulation for a poorly soluble drug and to develop a water-soluble oral formulation. Eg: prodrugs of tocopherol are synthesized to reduce the oxidation potential of tocopherol &also increase its water solubility. The reaction is simple with the drug being mixed with the suitable linker, and with suitable reaction conditions, a prodrug is obtained.

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Prodrugs to improve passive oral drug delivery : The linkers that improve the passive oral drug delivery are generally esters connected to carboxylic acids group or amino acid groups of water-soluble drugs. These molecules upon crossing the intestinal membranes are distributed and gets converted to original compound to elicit its action. Eg: foscarnet, disodium chromglycate, enalpril, losartan, NSAIDS like diclofenac, phenytoin etc .

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Prodrugs for targeted delivery : It includes targeting viruses with site selective activation. Eg: acyclovir Targeting the colon-eg: glycosidic and glucurodinic prodrugs Targeting the liver- eg: bile acid prodrugs Targeting with antibodies for anticancer molecules to target tumour cells.

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Polymeric Prodrugs : Numerous conjugates have been prepared for applications ranging from passive drug targeting to controlled release. Polymeric conjugates are grouped into two broad categories: permanent conjugates prodrugs Synthesis of ester conjugates Synthesis of carbonate conjugates Synthesis of carbamate conjugates Synthesis of C=N linkages Synthesis of amide prodrugs


PHARMACOKINETICS Rate limiting steps in the release of a drug from prodrug: controlled controlled release activation Prodrugs in Tissues Drugs in Tissues Prodrugs Prodrug in Blood Drug in Blood Prodrug Eliminated Drug Eliminated

Pharmaceutical Applications:

Pharmaceutical Applications The undesirable organoleptic properties and physico chemical problems can be resolved 1.Improvement of taste& odour 2.reduction of GI irritation 3.reduction of pain on injection 4.enhancement of drug solubility and dissolution rate 5.enhancement of chemical stability of the drug

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Prodrugs with improved taste: Parent drug Prodrug Chloramphenicol Palmitate ester Clindamycin Palmitate ester Sulfisoxazole Acetyl ester Prodrugs to reduce gastric irritation : Parent drug Prodrug Salicylic acid Salsalate,aspirin Diethyl stilbestrol Fosfestrol Kanamycin Kanamycin pamoate Nicotinic acid Nicotinic acid hydrazid

Pharmacokinetic Application:

Pharmacokinetic Application Enhancement of bioavailability Prevention of presystemic metabolism Prolongation of duration of action Reduction of toxicity Site specific drug delivery (drug targeting)


CONCLUSION This concept is used in the treatment of human beings in modern times only. Adenoviral vectors were the first homing devices used to target the genes into human cells. Their use has been marred by toxicity & lack of targeting. The recent innovation is to modify the properties of genes & increase their cellular delivery. The latest of such uses is the development of prodrugs for the genes.


REFERENCES Foye’s Principles of Medicinal Chemistry Pharmaceutical Dosage Forms and Drug Delivery Systems, Howard C.Ansel Oral Drug Delivery Technology, Okunuru Jithan The Theory and Practice of Industrial Pharmacy, Leon Lachman and Liebermann

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