Sometimes, ADME considerations can be used to the advantage of the drug designer.
This is particularly true when applied to the concept of a prodrug. A prodrug is a drug molecule that is biologically inactive until it is activated by a metabolic process. The active compound is released as a metabolite.
The purpose of a pro-drug can be to:
1. Increase or decrease the metabolic stability of a drug 2. Interfere with transport characteristics
Figure 3.9 The blood–brain barrier (BBB) is a major impediment to the delivery of drugs to the brain. In the brain, in order for a drug molecule to leave a capillary and successfully journey to a neuronal receptor, it must traverse multiple barriers. The walls of capillaries in the brain are dif-ferent from those in non-brain tissues. Tight junctions prevent the drugs from readily crossing the capillary. Next, in the brain, another type of cell, called an astrocyte, forms an additional barrier that must be traversed. Astrocytes are not present outside of the brain.
3. Mask side effects or toxicity 4. Improve the flavor of a drug
An ester, for example, can be used to “mask” a carboxylate. Within the body, the ester is hydrolyzed, releasing the drug in its bioactive carboxylate form.
3.5.3.1 Regulation of Drug Stability
The regulation of drug stability can take two directions: a prodrug can increase the in vivo stability of an active compound and prolong its action, or it can automatically limit its duration and prevent potential toxicity.
There are many examples of drug stabilization. Among local anesthetics, procaine (3.20) is an ester and is therefore very easily hydrolyzed by esterases. By conversion of the ester into an amide in lidocaine (3.21), the duration of action is increased sev-eral fold. Lidocaine is also used intravenously as an antiarrhythmic agent. In that application, it must pass through the liver — the principal drug-metabolizing organ — in which it loses an N–ethyl group to become a convulsant and emetic. To minimize these unwanted and toxic effects, tocainide (3.22) — whose α-methyl group prevents degradation, and which lacks the vulnerable N-ethyl groups — was prepared.
This compound is not a prodrug in the strict sense, but rather represents a molecular modification.
Replacement of a “vulnerable moiety” such as a methyl group by a less readily oxi-dized chlorine was used to transform the short-acting tolbutamide (3.23), an oral antidi-abetic, into the long-acting chlorpropamide (3.24), with a half-life sixfold greater than its parent.
A decrease in stability is often a desirable modification. For example, succinylcholine (suxamethonium; 3.25) — a neuromuscular blocking agent used in surgery — has a self-limiting activity, since the ester is hydrolyzed in about 10 minutes, prevent-ing the potential for overdose, which could be fatal with more stable curarizprevent-ing agents.
An ester group can be introduced into a local anesthetic, such as tolycaine (3.26), to prevent the drug from reaching the CNS if it is injected intravascularly by accident or abuse. The ester group is fairly stable in the tissues but is very rapidly hydrolyzed in the serum to the polar carboxylic acid, which cannot penetrate the blood–brain barrier.
3.5.3.2 Interference with Transport Characteristics
Interference with transport characteristics can serve many purposes. The introduction of a hydrophilic “disposable moiety” can restrict a drug to the gastrointestinal tract and prevent its absorption. Such a type of drug is represented by the intestinal disinfectant succinyl-sulfathiazole (3.27). On the other hand, lipophilic groups can ensure peroral activity, as in the case of the penicillin derivative pivampicillin (3.28), which enters the circulation and then slowly releases the antibiotic in its free acid form, producing high blood levels of the latter.
Lipophilic groups that are not easily hydrolyzed are used extensively for depot preparations, which liberate the active drug molecule slowly, for a period of days or weeks. Steroid hormone palmitates and pamoates, and antimalarial esters (e.g., cycloguanil pamoate, 3.29), can deliver the active drugs over a prolonged time; cycloguanil, for example, is released over a period of several months. This can be a great convenience for the patient, especially in areas with remote medical facilities.
Drug designers have attempted for many years to use selective drug-transport moi-eties, and have met with moderate success. The idea is to attach a drug, such as an anti-tumor agent, to a natural product that will accumulate selectively in a specific organ and act as a “Trojan horse” for the drug. The attachment of alkylating agents to estro-gens has been tried in the treatment of ovarian cancer, and amino acids have also been used as drug carriers. A recent ingenious application of the carrier concept is the uti-lization of antibodies — which can, at least in principle, be tailored to any site — as drug carriers. In this regard, antitumor agents such as adriamycin (3.30) and methotrexate (3.31) have been linked covalently to leukemia antibodies and melanoma antibodies, with some initial success. The large-scale preparation of antibodies is, of course, a major difficulty in this approach; however, the new monoclonal antibodies hold great promise.
3.5.3.3 Masking of Side Effects or Toxicity
Masking of the side effects or toxicity of drugs was historically the first application of the prodrug concept. This concept goes back to the turn of the twentieth century, and in fact many prodrugs were not at the time really recognized as such. For instance, castor oil is a laxative because it is hydrolyzed intestinally to the active ricinoleic acid.
However, the classical example is prontosil (3.32), which undergoes a reduction to sul-fanilamide. The analgesic phenacetin (3.33) acts in the form of its hydrolysis product,
p-acetaminophenol. Another classical example of side-effect masking occurs in aspirin (3.34) and its many analogs — the result of a considerable effort to eliminate the gastric bleeding caused by salicylic acid.
Selective bioactivation (toxification) is illustrated in the case of the insecticide malathion (3.35). This acetylcholinesterase inhibitor is desulfurized selectively to the toxic malaoxon, but only by insect and not mammalian enzymes. Malathion is therefore relatively nontoxic to mammals (LD50 = 1500 mg/kg, rat; p.o.). Higher organisms rapidly detoxify malathion by hydrolyzing one of its ester groups to the inactive acid, a process not readily available to insects. This makes the compound doubly toxic to insects since they cannot eliminate the active metabolite.
3.5.3.4 Improvement of Taste
Taste improvement is quite an important aspect of drug modification, especially in pedi-atric medicine. The extremely bitter taste of some antibiotics, such as clindamycin (3.36) or chloramphenicol (3.37), can be masked successfully by preparing esters or pamoate salts of these drugs, which are very insoluble and therefore have no taste.