Читать книгу Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulations - Sheila Annie Peters - Страница 34

When an active metabolite is part of a therapeutic strategy, the parent compound is called a prodrug. A prodrug is a pharmacologically inert compound that undergoes in vivo biotransformation to release the active drug by chemical or enzymatic cleavage at the desired site. Activation to the active compound should constitute the major pathway (>75%). Broadly, prodrugs can be classified into two types, carrier‐linked and bioprecursor prodrugs. A carrier‐linked prodrug comprises an inert carrier coupled covalently by an ester or amide linkage to an active drug. It is more lipophilic than the active drug. In a bioprecursor prodrug, the active drug is obtained by redox transformation by enzymes without alteration of its lipophilicity.

A prodrug strategy is employed for multiple reasons – to enhance bioavailability of poorly soluble drugs or drugs that are prone to extensive pre‐systemic metabolism, to reduce side effects of the active drug, to prolong duration of action or to enable drug targeting to desired sites. Prednisolone phosphate is a prodrug activated in vivo by phosphatase to prednisolone which is pharmacologically active and poorly water soluble. Propranolol is a widely used antihypertensive drug which has low oral bioavalability due to first pass metabolism. Its prodrug, hemisuccinate ester of propranolol, blocks the glucuronidation leading to an 8‐fold increase in the plasma levels of propranolol. To reduce the side effects mediated by the pre‐colonic absorption of the pharmacologically active anti‐inflammatory drug 5‐amino salicylic acid (ASA), it is coupled with diazotized sulphanilamide pyridine to its prodrug sulfasalazine. Sulfasalazine remains intact until it reaches the colon, where the azo reductase in the colonic microflora converts it to constituents entities, 5‐ASA and sulphanilamide pyridine making them available for colonic absorption. Prodrugs of nonsteroidaidal anti‐inflammatory drugs (NSAIDs) overcome the gastrointestinal toxicity (irritation, ulcergenocity, and bleeding) caused by the drugs (Shah et al., 2017). L‐dopamine, used for the treatment of Parkinson’s disease, cannot cross the blood–brain barrier to act on the central nervous system (CNS). Its prodrug levodopa can easily cross the blood–brain barrier via an amino acid carrier and is then decarboxylated into dopamine by dopa decarboxylase in the CNS. Prodrugs are also used for masking taste and odor to improve patient compliance. Understanding the pharmacokinetics of a prodrug and its metabolite is key to defining the prodrug dose needed for efficacy.