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Applications of mutual prodrug /utility of prodrugs 1.

decreased toxicity and adverse reaction a) carboxylic and phenols (too acidic) => converted to ester prodrugs

* ester prodrugs are activated by enzymatic hydrolysis *In the body, ester bond is readily hydrolyzed by ubiquitous esterases (carboxylesterases, paraoxonases, arylesterases) found in blood, liver and other organ. *Esters are more susceptible to hydrolysis by introducing electron-withdrawing group to the alcohol moiety. Inductive effect of these group aid in hydrolytic mechanism by making alcohol a better leaving group *if ester are too reactive, it becomes chemically unstable and hydrolyzed before it reaches the blood suply *advantage: i)enhance the lipophilicity ii)masking charged group of carboxylic acid/phosphates (increase passive membrane permeability) *disadvantage: accurate prediction of pharmacokinetic disposition in human( because there is significant differences in specific carboxylesterase activities in preclinical species and human) Eg: enalapril is prodrug for enalaprilate(anti-hypertensive agent) Pivampicillin is prodrug for penicillin -Alkyl and aryl ester prodrugs such as angiotensin-converting enzyme (ACE) inhibitors are in clinical use. -Disadvantage: slow and incomplete bioconversion of some simple alkyl ester in human blood result in lower than predicted bioavailability -overcome by double prodrug(pro-prodrug) that require an enzymatic breakdown after a spontaneous chemical reaction release the parent drug Eg: double prodrug are preferred in preparing oral acyloxyalkyl ester prodrugs of -lactam antibiotics. b) NSAID => blocking acidic function of it (devoid of gastric ulcerogenic) -convert carboxylic function of NSAIDs into ester -For amide mutual prodrugs, amino acids like L-tryptophan, L-histidine, L-glycine are used as carriers to produce anti-inflammatory effect. -Analgesic, anti-inflammatory drugs (paracetamol and salicylamide) are carriers to synthesize mutual prodrugs of NSAIDs c)phosphate ester as prodrug of hydroxyl / amine functionalities -aim: to enhance aqueous solubility for more favourable oral or parental administration Advantage: 1. presence of the dianionic phosphate promoiety raises the aqueous solubility 2. display excellent chemical stability 3. rapid conversion back to the parent drug by phosphatase present in intestine or liver -phosphate esters are hydrolyzed by alkaline phosphatases. Disadvantage: 1. a highly ionic phosphate prodrug show suboptimal enzymatic bioconversion by phosphatases (lead to precipitation of parent drug following cleavage in the intestinal lumen=>poor absorption/ drug flux of parent drug) 2. reduced bioavailability in the presence of calcium (eg: milk product/ antacid)

d. carbonates and carbamates as prodrug of carboxyl, hydroxyl or amine functionalities -Carbonate & carbamate=> presence of an oxygen/nitrogen on both side of carbonyl carbon -carbonate: derivative of COOH and OH -carbamate: carboxylic acid and amine derivative -enzymatically more stable than ester but more susceptible to hydrolysis than amides -requires esterases for parent drugs formation e. amides as prodrugs of carboxylic acid and amines -amide: derivative of amine and carboxyl functionalities -amide has high enzymatic stability in vivo (used to limited extend in prodrug design) -amide bond is hydrolyzed by uniquitous carboxylesterases, peptidases or proteases. -advantage: enhance oral absorption by synthesizing substrates of specific intestinal uptake transporters. f. Oximases as derivatives of ketones, amidines and guanidines -oximes are derivatives of ketone, amidines and guanidines - used to modify molecules that lack hydroxyl, amine or carboxyl functionalities -hydrolyzed by xenobiotic metabolizing enzymes -advantage: enhance the membrane permeability and absorption of a parent drug. g. Trojan horse approach for transport protein -Levodopa is a prodrug for dopamine(treat Parkinson). -It is more polar than dopamine. It takes advantage of transport proteins responsible for carrying amino acid to cross the cell membrane. -Once in the brain, a decarboxylase enzyme removes the acid group and release dopamine. h. N-methylated prodrugs -polar amine can be N-methylated to reduce polarity and improve membrane permeability -N-methylated prodrugs will undergoes N-Demethylation in liver -Several hypnotics and antiepileptics take advantage of this reaction, for example hexobarbitone 2. absorption and distribution a) improved oral absorption i) to overcome poor absorption a)enhance permeability by masking polar/ charged moieties of a poorly permeable parent drug. b) these prodrugs are often carboxylic acid ester and phosphonic acid esters (low permeablility but high solubility) c) these prodrug do not alter metabolic clearance(half-life of parent drugs) and has low to moderate clearance in preclinical species.) ii) to overcome parent drugs not significantly metabolized by liver (bioavailability) -limitation to oral bioavailability of a compound Aqueous solubility Low permeability Propensity to be an efflux substrate Rapid and extensive hepatic metabolism and biliary excretion -bioavailability is controlled by fraction absorbed (Fa)=>low Fa = low bioavailability - Fa is controlled by Gastrointestinal permeability Aqueous solubility

Dissolution rate Dose number

3. prodrugs to prolong drug activity -Prodrugs can prolong a drugs activity by converting slowly to the active drug. -eg 1: azathioprine is slowly converted to 6-mercaptopurine by being attacked by glutathione, allowing more sustained activity -The greater the electron-withdrawing power of the heterocyclic group, the faster the breakdown -NO2 group(in azathioprine) hence ensure an efficient conversion to 6-mercaptopurine -eg 2: Valium is a prodrug for nordazepam(a sedative ) that lead to a more sustained action -Deliberately associate a very lipophilic group to the drug can prolong drug activity -This mean most of the drug stored in fat tissue and if the lipophilic group is slowly released, then the drug is steadily and slowly released into the bloodstream. -eg 3: Cycloguanil pamoate(antimalarial agent) is bound ionically to an anion with a large lipophilic group. -eg 4: lipophilic ester of Fluphenazine is given by intramuscular injection and slowly diffuses from fat tissue into the blood supply where it is rapidly hydrolyzed. 4. Prodrugs masking drug toxicity and side effect Case 1: Salicyclic acid is a painkiller but causes gastric bleeding due to free phenolic group. This is overcome by masking the phenol as ester (aspirin). The ester is later hydrolyzed to free the active drug Case 2: -Prodrug pargylene can be converted to propiolaldehyde by enzyme in the liver. (Propiolaldehyde is useful in aversion therapy of alcohol but it is an irritant ) -Prodrug can be used to give a slow release of drugs that would be too toxic if taken directly Case 3: Cyclophosphamide is a non-toxic prodrug that can be safely taken orally. Once absorbed, it is metabolized by the liver to a toxic alkylating agent for cancer treatment Case 4: Acyclovir and penciclovir are non-toxic prodrugs that show selective toxicity towards virally infected cells. They are converted to toxic triphosphate by viral enzymes that present only in infected cell Case5: In the vein, oxamniquine(antischistosomal agent)is converted to alkylating agent by an enzyme present only in parasite 5. i) prodrug to lower aqueous solubility -revolting taste of drugs can be removed by reducing their water solubility so they do not dissolve on the tongue -the bitter taste of chloramphenicol (antibiotic) can be avoided by using palmitate ester. -the ester is more hydrophobic and does not dissolve easily on the tongue and is quickly hydrolyzed once swallowed.

ii) prodrug to increase water solubility -useful for drugs given intravenously (higher concentration and smaller volume) Eg1: succinate ester of chloramphenicol increase the water solubility due to the presence of extra carboxylic acid. Once the ester is hydrolyzed, chloramphenicol is released along with succinic acid which is naturally present in the body -preventing the pain associated with poor solubility of drug at the site of injection Eg2: clindamycin(antibacterial agent) is painful when injected, but phosphate ester prodrug improves solubility because of the ionic phosphate group and prevent pain. 6. Prodrugs to increase chemical stability -ampicilin (antibacterial agent) decomposes in conc. aqueous solution as a result of intramolecular attack of the side chain amino group on the lactam ring -Hetacillin is a prodrug which locks up the offending nitrogen in a ring and prevents this reaction. -Once the prodrug has been administered, hetacillin decomposes slowly to release ampicillin and acetone. 7. Prodrugs activated by external influence (sleeping agent) -conventional prodrugs are inactive compounds metabolized in the body to the active form. -sleeping agent is an inactive compound converted to active drug only by particular external influence -Eg: photodynamic therapy -porphyrin/chlorin (photosensitizing agent)is used in cancer treatment -they accumulate within cells and have some selectivity for tumour cells when given intravenously. -If the cancer cells are irradiated with light, porphyrins are converted to an excited state and react with molecular oxygen to produce highly toxic singlet oxygen. 8. to reduce poor patient acceptability (Reduction of gastrointestinal (GI) side effects and ulcerogenicity of NSAIDs (nonsteroidal antiinflammatory drugs) -NSAID produces GI side effects like gastric irritation, ulceration, bleeding, perforation and life threatening conditions -GI lesions produced by NSAIDs are generally attributed to either direct and/or indirect mechanisms. - The direct contact effects result usually from local irritation produced by free acidic group of NSAIDs and local inhibition of prostaglandin synthesis in GIT. - Indirect mechanism is due to generalized systemic action occurring after absorption and is demonstrated on intravenous dosing Example: 1. Benorylate is a mutual prodrug of aspirin and paracetamol, linked through ester linkage, has decreased gastric irritancy with synergistic analgesic action 2. Glycine methyl ester conjugate of ketoprofen 3. Histidine methyl ester conjugate of diclofenac 4. Conjugates of flurbiprofen with amino acid like L-tryptophan, L-histidine, phenylalanine and alanine as mutual prodrugs have less ulcerogenicity with better antiinflammatory/analgesic action than their parent drugs. 5. Mutual prodrugs of ibuprofen with paracetamol and salicylamide have better lipophilicity and reduced gastric irritancy than the parent drug

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