Metabolic Changes of Drugs Prof. Faris T. Abachi ( PHD Pharmacy) 3rd Year Pharmacy 2013

Susceptibility to Hydrolysis Hydrolytic Reactions Hydrolyzes (adds water to) esters and amides and their isosteres; the OH from water ends up on the carboxylic acid (or its isostere) and the H in the hydroxy or amine Enzymes: Non-microsomal hydrolases; however, amide hydrolysis appears to be mediated by liver microsomal amidases, esterases, and deacylases Electrophilicity of the carbonyl carbon, Nature of the heteroatom, substituents on the carbonyl carbon, and substituents on the heteroatom influnce the rate of hydrolysis In addition, Nucleophilicity of attacking species, Electronic charge, and Nature of nucleophile and its steric factors also influence the rate of hydrolysis Table: Naming carbonyl - heteroatom groups R1 R2 Name Susceptibility to Hydrolysis C O Ester Highest S Thioester Carbonate N Amide Carbamate Ureide Lowest

The Reactions Ester hydrolysis Amide hydrolysis (slower) Carbonate hydrolysis Carbamate hydrolysis Urea hydrolysis Hydrazide hydrolysis

Drug Examples Lidocaine

Stereoselectivity of Hydrolysis Etomidate (Amidate, hypnotic): R-(+)-isomer is more rapidly hydrolyzed, but S-(-)-isomer is more rapidly hydroxylated.

The Concept of Prodrugs and Antedrugs Prodrug: Need metabolic activation Antedrug: Active drug that is quickly inactivated thereby minimizing systemic effects

Prodrugs and Related Terms Albert in 1958 coined the term prodrug to refer a pharmacologically inactive compound that is metabolically activated in the mammalian system Hard Drugs are not susceptible to metabolic or chemical transformation, have high lipid solubility and thus accumulation or high water solubility Celecoxib: t1/2 10-12 h in humans t1/2 ca. 680 h (Liver toxicity) Soft drugs are active compounds that after exerting its action undergo inactivation to give a nontoxic product. Indeed soft drugs are a group of modified compounds that are also designed to delivery the drugs in to the brain (the chemical delivery system). Bodor coined the term. Ce

Basic Concepts of Prodrugs Carrier-linked prodrugs: a pro-moiety is attached, which is not necessary for activity but may impart some desired property to the drug, such as increased lipid or water solubility, or site-directed delivery Advantages may include: increased absorption alleviation of pain at the site of injection if the agent is given parenterally elimination of an unpleasant taste associated with the drug decreased toxicity decreased metabolic inactivation increased chemical stability prolonged or shortened action Bioprecursor prodrugs contain no pro-moiety but rather rely on metabolism to introduce the functionality necessary to create an active species

Prodrug: Prednisolon Hemisuccinate Sodium Salt Prodrug: Chloramphenicol Hemisuccinate Na Salt Prodrug: Prednisolon Hemisuccinate Sodium Salt Inactive as it is and activated by hydrolysis by plasma esterases to chloramphenicol/ prednisolon Increased water solubility for parenteral administration, which otherwise would precipitate and cause pain by damaging surrounding tissues Prodrug: Chloramphenicol Palmitate Prodrug: Clindamycin Palmitate Inactive as it is; activated by hydrolysis by intestinal esterases to chloramphenicol/ clindamycin Minimize their bitter taste and improve their palatability in pediatric liquid suspensions

Prodrugs of Functional Groups Carboxylic acids and alcohols: Most common Amines and azo linkages: Not been used much Carbonyl compounds: Not found to be used widely

Carboxylic Acids and Alcohols Converted to ester prodrugs which are often hydrolyzed to active drug by different types of esterase enzymes: Ester hydrolase Lipase Cholesterol esterase Acetylcholinesterase Carboxypeptidase Cholinesterase Microflora in the gut Manipulation of steric and electronic properties of promoiety allows control of rate and extent of hydrolysis

Advantage of Prodrug Formation I: Increased absorption of hydrophilic drugs by making less hydrophilic or more lipophilic Prodrug of Epinephrine: Dipivefrin More lipophilic, thus achieve higher intraocular concentration Hydrolysis occur in cornea, conjunctiva, and aqueous humor after ophthalmic application

Not all carboxylic esters hydrolyzed in vivo where double ester approach is used