Prodrugs: list, types, objectives and methods of prodrug designing

prodrugs list

Prodrugs are described as inactive drugs that must be changed into one or more active metabolites within the body in order to exert the desired pharmacological effect. The prodrug may be more stable, have greater bioavailability, or other desired pharmacokinetic features, or have fewer side effects and toxicity than the active form. Some prodrugs are activated selectively at the site of action.

Prodrugs list

ANS

  • Dipivefrine – epinephrine
  • Levodopa – dopamine
  • a-Methyldopa – a-methylnorepinephrine
  • Fesoterodine – tolterodine
  • Droxidopa – norepinephrine
  • Midodrine – desglymidodrine
  • Lisdexamphetamine – d-amphetamine
  • Bambuterol – terbutaline

NSAIDS

  • Nabumetone – 6-MNA
  • Parecoxib – valdecoxib
  • Sulindac – sulfone metabolite

Corticosteroids 

Prostaglandins

Latanoprost – PGF

Antiepileptics

  • Fosphenytoin – phenytoin
  • Oxcarbazepine – S-licarbazepine
  • Carbamazepine – carbamazepine-10,11-epoxide

Antihypertensive

  • All ACE inhibitors except captopril and lisinopril
  • Minoxidil – minoxidil sulfate
  • Candesartan cilexetil – candesartan
  • Olmesartan medoxomil – olmesartan
  • Azilsartan medoxomil – azilsartan

Kidney (vasopressin analogue)

Terlipressin – vasopressin

Anticoagulants

  • Dabigatran etexilate – dabigatran
  • Clopidogrel – Clopidogrel Bisulfate
  • Ticlopidine – undetermined metabolite
  • Prasugrel – R-138727

Anti- dyslipidaemics

  • Fenofibrate – fenofibric acid,
  • Fosaprepitant – aprepitant
  • Simvastatin – β-hydroxy acid metabolite

Antidiarrhoeal drugs

Racecadotril – thiorphan

Opioids

Codeine – morphine

Antimicrobials

  • Prulifloxacin – ulifloxacin
  • Bacampicillin – ampicillin
  • Cefpodoxime proxetil – cefpodoxime
  • Ceftamet pivoxil – ceftamet
  • Nitazoxanidetizoxanide
  • Sulfasalazine – sulfapyridine & 5-ASA
  • Olsalazine – sulfapyridine & 5-ASA
  • Balsalazide – sulfapyridine & 5-ASA
  • Melarsoprol – melarsen oxide
  • Chloramphenicol succinate – chloramphenicol
  • Clindamycin palmitate – clindamycin
  • Tedizolid phosphate – tedizolid
  • Isoniazid – N-acetyl isoniazid
  • Pretomanid – des-nitro metabolite
  • Delamanid – des-nitro metabolite

Antivirals

  • Valacyclovir – acyclovir (acyclovir triphosphate)
  • Famciclovir – 6-deoxy penciclovir
  • Valganciclovir – ganciclovir
  • Oseltamiviroseltamivir carboxylate
  • Tenofovir disoproxil – Tenofovir
  • Adefovir dipivoxil – adefovir
  • Sofosbuvir – GS-461203
  • Fosamprenavir – amprenavir

Anticancer drugs

  • Capecitabine – Fluorouracil (5-FU)
  • Irinotecan – SN-38
  • Mercaptopurine – methylmercaptopurine
  • Zidovudine – zidovudine triphosphate

Immunosuppressant drugs

  • Mycophenolate mofetil – mycophenolic acid
  • Azathioprine – 6-mercaptopurine
  • Leflunomide – A77-1726

Drugs for psoriasis (retinoids)

Tazarotene – tezarotenic acid

Anaesthetic drugs

Fospropofol – propofol

Types of prodrugs

Type 1

Prodrugs that are bioactivated intracellularly, subdivided into following subtypes –

  • Type 1A: bioconversion to active metabolite takes place in therapeutic target cells, e.g., levodopa, acyclovir, 5-flurouracil, zidovudine etc.
  • Type 1B: converted to active metabolite in cells of metabolic organ/tissue (liver, lung, GI mucosa), e.g., carbamazepine, captopril, clopidogrel.

Type 2

Prodrugs that are bioactivated extracellularly, subdivided into following subtypes –

  • Type 2A: drugs are activated in GI fluids, e.g., sulfasalazine, lisdexamphetamine, loperamide oxide.
  • Type 2B: drugs are activated within systemic circulation and other ECF, e.g., bambuterol, bacampicillin, Fosphenytoin, dipivefrine.
  • Type 2C: drugs are activated extracellularly near therapeutic target cells/tissue, e.g., antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), virus-directed enzyme prodrug therapy (VDEPT).

Objectives of prodrug designing

Pharmaceutical objectives

  • Improve solubility: Chloramphenicol succinate is used as an intravenous prodrug of chloramphenicol, because active chloramphenicol is not dissolved in water.
  • Improve GI tolerance: Several drugs like NSAIDS cause gastric irritation and interfere with protective gastric mucosal layer. Benorylate, which is a mutual prodrug of aspirin and paracetamol, has less prone to such symptoms. Another example is salsalate, a prodrug of salicylic acid.  
  • Improve chemical stability: To make acid stable at gastric pH. Azacytidine hydrolyses readily in gastric pH but the bisulphite prodrug of it is more stable. Another example is sulfasalazine used for the treatment of ulcerative colitis.
  • Decrease pain at site of administration: Some drugs, such as phenytoin and clindamycin, produce pain when injected intramuscularly. Poor aqueous solubility or a weakly acidic nature could be the reason. This can be overcome by formulating their salts, phenytoin phosphate and clindamycin phosphate.
  • Taste improvement: One of the key factors in patient acceptance is taste. Prodrug design can reduce a drug’s bitter taste, for instance, chloramphenicol palmitate.

Pharmacokinetic objectives

  • Increase GI absorption and bioavailability: GI absorption of a drug is improved by the addition of a hydrophobic group; for example, pivampicillin, bacampicillin, and talampicillin have higher bioavailability than their parent drug, ampicillin.
  • Increase organ/tissue selective delivery: Only in the target organ or tissue, the prodrug undergo conversion to its active metabolite; either a particular enzyme is used, or a pH level other than the normal pH for activation. As in example of ciclesonide, lung-specific esterases can convert it to its active form
  • Increase biological half-life: Long-chain aliphatic esters are frequently used in the creation of sustained release preparations because their esters hydrolyze slowly, Such as lisdexamphetamine and steroid ester prodrugs (testosterone propionate, estradiol propionate).
  • Improve membrane transport: Levodopa is utilized as a prodrug of dopamine in the treatment of parkinsonism since dopamine cannot penetrate the blood-brain barrier.

Pharmacodynamic objectives

To decrease toxicity and improve therapeutic index of a drug.

Methods of prodrug designing

Prodrug designDescriptionExamples
1. BioprecursorsProdrug is obtained by chemical modification of active drugPhenylbutazone, a metabolic precursor of oxyphenbutazone
2. Carrier linkedBy using an ester or amide linkage, an active drug is covalently attached with an inert carrier 
a) Pro-prodrug (tripartite prodrug)A prodrug that was derived in a manner that required enzymatic conversion before prodrug metabolism could produce the active drugHypoxia sensitive targeted cancer therapy, cefpodoxime proxetil 
b) MacromolecularLarge-molecular-weight substances like polysaccharides, proteins, polymers, and cyclodextrins are employed as carriers.Naproxen-2-glyceride
c) Mutual prodrugTwo active drugs are combined with each otherEstramustine, a mutual prodrug of 17-alpha-estradiol & nor-mustard.   Benorylate, a mutual prodrug of aspirin and paracetamol
d) site specific prodrugThe prodrug is converted into its active metabolite only in target organ/tissueSulfasalazine, ciclesonide
table of prodrug design

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