The hydrophilic a n d lipophilic characteristics of drugs are often of impor
tance t o t h e pharmacologist in his efforts t o prepare drugs with properties suitable for special applications. I n storage-depot preparations, intended for intramuscular injection, increased lipophilic properties m a y be of advantage.
I n order to obtain water-soluble compounds suitable for intravenous injections, an increase in hydrophilic properties m a y be necessary.
As far as alcohols are concerned, t h e esterification with monocarbonic acids leads, as a rule, t o an increased fat-solubility, while t h e production of hemi-esters with dicarbonic acids leads t o an increased water-solubility. Often t h e esters, as such, will be inactive, which is understandable because specific groups in t h e drug molecule are masked. The esterification is only permissible in preparations of t h e drug for use if esterases in t h e body bring a b o u t hydroly
sis with sufficient rapidity t o reach effective plasma concentrations of t h e free drug. Examples of storage-depot preparations based on increased lipophilic properties are t h e esters of hydrocortisone a n d t e r t i a r y butylacetic acid or cyclopentylpropionic acid, and esters of testosterone a n d phenylpropionic
84 Ε. J . ARIENS AND A. M. SIMONIS
acid (102, 103, 104, 217). Examples of water-soluble esters suitable for intra
venous injection are hemiesters of succinic acid and hydrocortisone, pred
nisolone and the anesthetic steroid, hydroxydionium.
I n the case of t h e hemisuccinic amides of sulfonamides, for instance, suc-cinylsulfathiazole, which are used against intestinal infections, the aim is t o decrease the rate of absorption of t h e drug from t h e gut. The sulfonamide must be liberated before it can develop its antimicrobial action. This time the hydro-lytic enzymes in t h e contents of t h e gut effect t h e bio-activation by hydrolysis.
Quaternization of amines decreases t h e action of these drugs on the central nervous system and restricts their distribution to extracellular space, and vice versa (96,224). Food additives, for example dyes, have t o be pharmacologically
butter yellow methyl orange
carcinogenic non-carcinogenic FIG. 9. Influence of the introduction of strong acidic groups on toxicity. Reith (157).
inert. They become so if their hydrophilic character is increased by introduc
tion of strong, acidifying sulfonyl groups (see Fig. 9). Carcinogenicity, which probably requires an intracellular action of t h e drug, also can be reduced in this way (157). Introduction of quaternary ammonium groups is less useful, because t h e t y p e of compounds t h u s obtained, although mainly restricted to extracellular space, is pharmacologically active, interfering with t h e action of acetylcholine on t h e cell membranes. Many curariform drugs, ganglionic blocking agents, and parasympatholytics are quaternary ammonium com
pounds. For cytostatic or carcinostatic drugs, an appreciable proportion of t h e nonionized form is required since t h e y have t o penetrate t h e cell. Highly dissociated compounds such as sulfonic acid and quaternary ammonium derivatives are inactive (161a).
If an ester or amide configuration in t h e drug molecule is essential to its pharmacological action, an especially rapid hydrolysis by t h e body enzymes leading t o a rapid breakdown and inactivation m a y serve as a principle for
Ι , Ι . Β . DRUG T R A N S F E R E N C E : DRUG METABOLISM 85 making short acting or ultra-short acting drugs. Examples are t h e curariform drugs, succinylcholine, a n d prestonal (162), a n d t h e ultra-short anesthetic, 2-methoxy-4-allylphenoxyacet-iV,iV-diethylamide (195).
On t h e other hand, one m a y t r y t o stabilize t h e ester or amide configuration in order t o obtain drugs with a more prolonged action. A well-known example is acetylcholine, which is rapidly hydrolyzed. β-Methylcholine and carb-aminoylcholine are less sensitive t o t h e acetylcholinesterase. The ester con
figuration in acetylcholine m a y even be replaced by structures indifferent t o
V XV- C - C — N H2
phenylethylamine ι amine o x i d a s e
ι 1 1 C ι
amphetamine: resistant to and inhibitor of the amine
oxidase
H O- v y - c — c — , C —O H
t o
dihydroxyphenylalanine [ decarboxylase
ι
H2N l
a -methyldihydroxyphenylalanine r e s i s t a n t to and inhibitor of the
decarboxylase
FIG. 10. Influence of "packing" of vital groups in drugs on their action.
t h e hydrolytic enzymes with maintenance of t h e pharmacological activity.
Examples are methylfurmethonium, methyldilvasene, and muscarine (see Table X V I , Section II.A.5.1). As mentioned before, substitution of an amide group for t h e ester group, or a-substitution in t h e acid and/or in t h e alcohol in t h e ester, often leads t o a stabilization of t h e drug and is tolerated in a number of cases without an essential change in t h e pharmacological properties of t h e drug (123). This is also true for ortho substitutions in various benzoic acid derivatives and anilides (50, 124, 172, 173, 194a).
N o t only can drugs be made more resistant t o hydrolysis b u t also t o other catabolic attacks. I n this respect t h e " p a c k i n g " of t h e vital groups has already been mentioned. An example is t h e introduction of a methyl group in
86 Ε . J . A R I E N S AND Α. Μ. SIMONIS
α-position to t h e amino group of /?-phenylethylamine. Phenylisopropyl-amine is obtained (Fig. 10). If both compounds are tested for their stimulating action by measuring t h e locomotor activity of mice after intraperitoneal injec
tion, amphetamine is found t o be very active, while phenylethylamine is not.
After inhibition of t h e amine oxidase by a suitable blocker, iproniazid, phenyl
ethylamine acts as a stimulant (Fig. 11). This probably results from decreased deamination of phenylethylamine, and, t h u s , effective concentrations of this compound can be reached in t h e brain (169).
FIG. 11. Action of various doses of amphetamine and phenylethylamine on the motility of mice. Note that phenylethylamine has only a slight activity. After iproniazid, it becomes much more active, van der Schoot (169).
The herbicide 4-chloro-2-methylphenoxyacetic acid is inactive with respect to certain dicotyledonous weeds. This appears t o be due t o a rapid oxidation of t h e acetic acid group. Introduction of an α-methyl group in t h e acetic acid moiety of t h e compound blocks this degradation. The compound t h e n is active in controlling t h e weeds mentioned (119a).
An especially interesting t y p e of protection of drugs against metabolic breakdown is t h e introduction of a terminal u n n a t u r a l (D) amino acid in biologically active polypeptides as, for instance, angiotensin I I . Such com
pounds m a y become indigestible then to the peptidases—in this case angio-tensinase, concerned with t h e degradation (38dy 171a). Such changes in n a t u r a l polypeptides, however, m a y bring a b o u t t h e risk of t h e introduction of antigenic activity.
Differences in drug sensitivity applied to biological systems which include more t h a n one species, m a y result in a "selective toxicity." This is, as formu
lated by Albert (3), an injury of certain species of living m a t t e r (uneconomic) without harming other species (economic). The t r e a t m e n t of infectious diseases, chemotherapy, t h e use of insecticides in t h e fight against t h e vectors of
infec-Ι , infec-Ι . Β . DRUG T R A N S F E R E N C E : DRUG METABOLISM 87 tious diseases, t h e use of weed-killers a n d fungicides in agriculture, etc., are based on selective toxicity due to differences in t h e biochemistry of t h e different species concerned (82c, 143, 143a). Examples of such differences a r e :
1. Differences in essential metabolites and, therefore, differences in anti
metabolite sensitivity. The use of t h e sulfonamides, antimetabolites of p-aminobenzoic acid, is based on this.
2. Many parasitic worms depend for their energy supply on anaerobic glycolysis. For this reason t h e y have, in contradistinction t o t h e hosts, t o convert relatively large quantities of glucose t o pyruvic acid, lactic acid, a n d other acids. The parasites are, much more t h a n their hosts, susceptible t o drugs t h a t inhibit anaerobic glycolysis. This also applies t o certain flagellates a n d flukes.
3. Differences in resorption. Certain vermicides, e.g., phenothiazine, are t a k e n u p more easily by t h e worms t h a n by t h e hosts.
4. Differences in metabolism. Trypanosoma equiperdum readily converts 6-azauracil into 6-azauridylic acid, a p o t e n t inhibitor of orotidylic acid decarboxylase. This results in a profound suppression of growth of this micro
organism. I n m a m m a l s , t h e capacity to convert 6-azauracil is very limited (163a).
Resistance t o chemotherapeutic compounds, as observed in certain strains of parasites, is often due t o differences in biochemical response (82c). The in-activation of penicillin by penicillinase-producing strains of bacteria, results in resistance of these strains t o penicillin. The resistance of houseflies t o certain organophosphates appears t o be due t o t h e presence of detoxicating enzymes,
" m u t a n t ali-esterases," able t o bind a n d inactivate these drugs (144a).
An interesting practical aspect of drug metabolism is t h e introduction of certain substituents, especially hydroxyl groups, in t h e steroid nucleus by various microorganisms. The point of a t t a c k in t h e steroid varies greatly a n d m a y be r a t h e r specific for certain microorganisms. The j8-hydroxylation a t carbon a t o m 11 is very difficult as a chemical procedure b u t is performed with ease by a variety of microorganisms a n d t h e enzymes obtained from t h e m . This made possible t h e large scale production of t h e hormones cortisone and hydrocortisone. Many enzymes t h a t are available for other hydroxylations have been obtained from microorganisms (201, 204). The same is t r u e for dehydrogenation reactions (192).
A special aspect of bio-activation of drugs is t h e possibility of using t h e high concentration of an enzyme in a particular tissue t o concentrate t h e drug.
Prostate tissue is rich in phosphatases; estrogens are used as therapeutic agents against cancer of this organ. This is plausible since t h e estrogens decrease t h e rate of growth of prostate tissue. P h o s p h a t e esters of t h e estrogens are supposed t o be split especially rapidly in prostate tissue because of its high concentration of phosphatases. I n t h a t case t h e result is a high local concentration of t h e active compound where it is particularly wanted (31). This could be termed a
88 Ε. J . ARIENS AND A. M. SIMONIS
biological localization of t h e therapeutic agent. Analogously, t h e cytostatic mitomen, inactive as such, is reduced and converted into t h e active form in t h e body, possible preferentially in t h e relatively poorly oxygenated cancer tissues (31, 57,166)—a bio-activation by t h e target tissues. Among t h e various papers in this field (64, 215), t h e discussion of t h e aspects of this principle as given by Harper (86) in his paper on " d r u g latency " and by Ross (161a) in a chapter on
" l a t e n t a c t i v i t y " are of special interest.
As mentioned previously, t h e enzymes in t h e endoplasmatic reticulum of t h e liver cells are intimately involved in t h e detoxication reactions. Consequently, hepatic damage brought about by substances such as tetrachloromethane (carbontetrachloride) or subtotal hepatectomy m a y result in an increased toxicity of, or sensitivity to, drugs such as barbiturates (177). Some of t h e clinical liver-function tests are based on t h e metabolic capacity of t h e liver t o alter or excrete drugs such as benzoic acid and bromosulfophthalein. Malignant degeneration of liver tissue, too, m a y lead to a loss of metabolic functions and, therefore, to an increase in drug toxicity (113c, lb).
Newborn infants are found t o be more sensitive to certain drugs. This has t o be a t t r i b u t e d partly to a deficiency in t h e enzyme systems responsible for detoxication. The insufficiency of t h e glucuronide conjugation system in new
borns results in a relatively high toxicity of chloramphenicol (191a, 209) a n d of progesterone (112). These drugs are detoxicated by conjugation with glucuronic acid. Also, t h e glucuronic acid conjugation of JV-acetyl-p-aminophenol is retarded (202). The same obtains for t h e acetylation of sulfonamides in t h e neonatal period (67).
A high fraction of drugs is often absorbed to plasma proteins. The absorbed drug is then protected against metabolic changes, b u t is unable t o induce pharmacological effects. The drug bound t o t h e proteins serves as a store which is in equilibrium with t h e free drug. The consequence is a prolongation of t h e activity of drugs which are bound t o plasma proteins t o a high degree.
An example of long-acting compounds of this t y p e are t h e newer sulfonamides, sulfaphenylpyrazole and sulfamethoxypyridazine (6, 38, 140, 168, 218).
As mentioned in Section LB.3.2, m a n y sulfonamides, e.g., sulfamethoxy
pyridazine, are excreted in t h e urine mainly in t h e form of t h e badly soluble Ar4-acetyl derivatives; a smaller fraction is conjugated to a glucuronide. One of t h e new long-acting sulfonamides, viz., sulfadimethoxine is coupled mostly to t h e highly soluble glucuronide (115b).
The changes in drug sensitivity as caused by adaptive changes in the q u a n t i t y of degrading enzyme (Section LB.2.4) m a y last for m a n y days.
Sensitivity to barbiturates such as hexobarbital a n d eunarcon is reported to be decreased for a period of 30 days after p r e t r e a t m e n t with a-hexachloro-cyclohexane (117a, 173b).
In future more attention should be paid to the m u t u a l influences in t h e actions of drugs given in sequence. Possibly a p a r t of the variation in drug
Ι , Ι . Β . DRUG T R A N S F E R E N C E ; DRUG METABOLISM 89 sensitivity now ascribed to biological variation m u s t be interpreted on the basis of the variation in the " d r u g h i s t o r y " of t h e individual patients.
The s t u d y in patients of the excretion products of drugs a n d of t h e r a t e of excretion before and after general anaesthesia m a y supply valuable informa
tion as far as clinical implications of drug-induced changes in drug metabolism are concerned. The same obtains for drug metabolism in patients t r e a t e d chronically with drugs such as phenobarbital, antiepileptics, etc.
An annoying aspect of t h e species differences in drug metabolism is the fact t h a t toxicological studies in animals cannot guarantee nontoxicity of the drug for men. A well-known example is the carcinogenic action of /3-naphthylamine in m a n and dog, caused by t h e metabolite α-hydroxy-β-naphthylamine (see Section I.B.3.2) and the absence of such an action in t h e rat, rabbit, a n d ape, which species metabolize t h e drug along another route (195a,b). Possibly t h e species differences in toxicity of t h e teratogen thalidomide, too, m u s t be ascribed to differences in metabolism (66b, 174a).