Metabolism of cocaine




Author: Fernando MONTESINOS A.
Pages: 11 to 17
Creation Date: 1965/01/01

Metabolism of cocaine

Dr. Fernando MONTESINOS A. Professor of Experimental Pharmacology and Biological Valuation of Medicinal Products, Faculty of Pharmacy and Biochemistry of the San Marcos National University, Lima, Peru

The problem of the coca leaf in Peru is one of national significance; for that reason the study of the problem, viewed from any standpoint, is always of topical importance and interest.

Carranza [ 5] * has said that the habit of coca leaf chewing is an unsolved problem for which no satisfactory scientific explanation has yet been given. It is because we share his view [ 28] that we have carried out the present study, and although it may not be as exhaustive as we had intended, it will, we are convinced, be a useful work which may serve as a basis for more thorough research.

The study is based on work carried out in the pharmacological laboratory of the Faculty of Pharmacy and Biochemistry of the San Marcos National University, Lima, Peru, by the following pharmaceutical and chemical research workers: Aguayo Sánchez [ 1] , Aguirre Arica [ 2] , Castañeda Pérez [ 6] , Cutipa Flores [ 11] , Cuzquín Mendoza [ 12] , Chang [ 13] , Herrera Orosco [ 21] , Jara Echea [ 27] , Montesinos Ampuero [ 26] [ 27] [ 28] , Pardo Arguedas [ 29] , Parra Garcia [ 30] , Vega Godoy [ 34] and Zapata Rivas [ 37] , on cocaine and its components, benzoyl-ecgonine and ecgonine, for the purpose of finding a scientific explanation of the metabolism of cocaine in a person addicted to coca leaf chewing.

This aspect of the cocal leaf problems was only touched upon lightly, without any definite conclusions being reached, by the Commission of Inquiry on the Coca Leaf in 1950 [ 23] . The Consultative Group on Coca Leaf Problems which met at Lima in 1962 [ 22] did not consider this aspect. The United Nations bodies concerned were chiefly interested in studying the problem in its medical, social, economic or administrative aspects.

Our study is divided into two parts:

Part 1: Physical and chemical study of cocaine and its hydrolysis products.

Part 2: Probable metabolism of cocaine in the habitual coca leaf chewer.

* References are to works listed in the Bibliography.

Physical and chemical study of cocaine and its hydrolysis products

It must be remembered that cocaine is, chemically speaking, methyl-benzoyl-ecgonine, the full formula of which is

H 2C
H 2C
CH 2

It is an unstable substance in contact with acids, bases, diastases, high temperature etc. which split it, firstly into benzoyl-ecgonine and methanol:

H 2C
H 2C
CH 2

and finally into ecgonine and benzoic acid:

H 2C
H 2C
CH 2

chemical phenomena of hydrolysis which are well-known in the laboratory and which, as we shall see, also take place in animal organisms.

In determining the spectral absorption curve in the ultra-violet region of cocaine hydrochloride, we found its two peaks at 233 and 275 millimicrons [ 26] . Subsequently the present writer and Jara Echea [ 27] determined the extinction coefficient of cocaine hydrochloride at 233 millimicrons, obtaining a value approximately the same as that found by Elvidge [ 14] :

. 233 millimicrons = 450
1 cm    

Using Ringbom's method to fix the optimum accuracy zone for determinations in the 233 millimicrons wavelength, we found it to be between .25 mg per cent and 2.5 mg per cent, with a relative error of .586 per cent. The determinations can however be carried out with greater or less concentrations than those mentioned, as we proved by detecting 50 gammas per cent, tolerating of course a greater error than that indicated by Ringbom.

Zapata [ 37] , applying the method proposed, has worked out a process for qualitative and quantitative detection of cocaine in the blood and urine of animals by experiments carried out in vitro and in vivo.

Realizing the implications of this investigation, we then undertook a thorough bibliographical search for works on the coca leaf and its alkaloids, and particularly on the splitting of cocaine, the principal alkaloid of the coca leaf, into its components, benzoyl-ecgonine and ecgonine, a subject which has greatly interested us from the beginning. We were thus able to collect 154 works dealing specifically with this topic. In this bibliographical review we were surprised to find that Castille [ 7] had already in 1925 determined the absorption spectrum of cocaine, finding the same peaks as those indicated by us. Castille arrived at that conclusion in an attempt to apply the spectrographic method in toxicology after injecting into laboratory animals: rabbits, guinea-pigs, dogs, etc. large doses of alkaloids and then extracting them or their hydrolysis products from the tissues in which they had lodged, and finally identifying them by spectrographic analysis. In this way he determined, apparently for the first time, the absorption spectrum of cocaine, comparing its peaks with those of benzoic acid and establishing the fact that they are due to the letter's molecule, thus confirming the original theory expounded to the same effect by Hartley and Hodley [ 18] .

We also find that Strait and Aird [ 32] identify cocaine in the brain tissue of animals which have been injected, using its absorption power on the 277 millimicrons wavelength and detecting it in small proportions like 12 gammas in 12 g. of tissue with satisfactory precision, according to the authors.

Herrera Orosco [ 21] studies the physical and chemical properties of the products into which cocaine may be split: benzoyl-ecgonine and ecgonine. He shows that benzoyl-ecgonine, which represents the first stage in splitting cocaine, does not precipitate with picric acid or with the reagents of Bouchardat and Yaborowsky but produces characteristic crystallized precipitates with the Mayer, Dragendorff, Sonnenschein, Bertrand, chloroauric and Reinnecke reagents. He studies its physical properties: the form of crystallization, solubility, optical rotation etc. He traces its spectral absorption curve in the ultra-violet region, finding a peak of maximum ab- sorption at 275 millimicrons. He shows that the benzoyl radical is the one which imparts to the molecules of benzoic acid, benzoyl-ecgonine and methyl-benzoyl-ecgonine, the property of absorbing this wavelength; that the detection of benzoyl-ecgonine by spectrophotometry is possible even in concentrations which cannot be determined by chemical processes; and that its extinction coefficient is

. 275 millimicrons = 222
1 cm    

Moreover Herrera determines the physical properties of ecgonine hydrochloride as regards form of crystallization, solubility, optical rotation, zone of fusion etc. He also finds that in contact with the general reagents of the alkaloids it behaves like its predecessor: that is to say, it does not precipitate with the Mayer, Bouchardat, picric acid and Yaborowsky reagents, but produces crystallized precipitates with the Dragendorff, Sonnenschein, chloroauric and Reinnecke reagents. The crystals of ecgonine Reinneckate are characteristic and serve to identify it; they could also be used for its quantitative determination by gravimetry.

Chang [ 13] working with Reinnecke's reagent demonstrates that the latter forms, with certain alkaloids, including cocaine, crystals of characteristic shapes which are insoluble, properties which facilitate its fairly exact identification and quantitative determination.

Continuing our efforts to find the most rapid and accurate methods for the separation, identification and quantitative determination of cocaine and its metabolites, we tested with Castañeda [ 6] the chromatographic process of Klementschitz and Mates [ 25] . We thus succeeded in accurately separating and identifying them, using as solvent normal butanol with acetic acid and obtaining the following Rf:

0.51 for cocaine hydrochloride

0.11 for benzoyl-ecgonine hydrochloride

0.05 for ecgonine hydrochloride

Applying the densitometric method to the spots revealed on the chromatograms, it is possible to detect even one gamma of cocaine hydrochloride, 4 of benzoylecgonine hydrochloride and 10 of ecgonine hydrochloride. This process, apart from being used in the detection of cocaine and its metabolites in organic liquids and tissues, could also be used in determining the degree of purity of the cocaine hydrochloride.

Aguirre [ 2] makes a more thorough study of benzoylecgonine, determining its physical and chemical properties: zone of fusion, solubility, specific rotatory power, etc.; in addition, he traces its absorption curve in the ultra-violet region, finding this time two peaks at 231 and 275 millimicrons. He establishes three analytical methods of detecting it quantitatively:

  1. By its benzoyl radical;

  2. By its precipitation with silicotungstic acid; and

  3. By precipitation with Reinnecke's salt.

Almost simultaneously Pardo [ 29] finds that cocaine and ecgonine are capable of precipitation with Reinnecke's salt and phosphotungstic acid. The latter had already been suggested by Hazard [ 19] . According to Pardo the detection of cocaine in the state of silicotungstate has a maximum error of 2.61 per cent and ecgonine 2.4 per cent.

Torricheli [ 33] affirms that ecgonine possesses an amphoteric property imparted to it by its OH and COOH groups; it is highly soluble in water, in acid solutions and in alkalines, and is insoluble in ether, chloroform and other solvents. It cannot like cocaine be extracted from its alkaline solutions by means of ordinary dissolvents and, as a means of determining its quantity, he suggests its reaction in chloride of sodium or potassium and chloroplatinic acid, with formation of iodine platinate of ecgonine (C9 H15 03 N.H1) 2 Pt. I 4, insoluble in glacial acetic acid; this constitutes a gravimetric process of great precision.

Probable metabolism of cocaine in the habitual coca chewer

Although our purpose is simply to explain the possible metabolism of cocaine in the habitual coca chewer when the alkaloid enters the organism through the mouth, I think it is of interest to explain first its effects on the animal organism when it is administered parenterally, in order to establish comparisons between the two effects.

Injected into a dog's veins in small doses, it rapidly reaches the brain tissue and produces a noticeable stimulus of co-ordinating ability and a characteristic euphoria. Administered in larger doses it produces a real psychomotor stimulation which is difficult to counteract even with highly sedative drugs. Lastly, with very large doses a special state is reached known as cocaine catatonia. These are stimulating and depressive effects on different sectors of the cerebro-spinal axis which have been fully demonstrated by Gutiérrez Noriega [ 17] and Zapata Ortiz [ 38] .

Woods [ 35] , using his own colorimetric method [ 36] , finds that cocaine injected in the proportion of 20mg Kg remains partially in the blood between 6 and 11 hours and the remainder in the tissues, particularly the renal tissues.

Strait, Aird and Weiss [ 31] [ 32] demonstrate by spectrographic processes that part of the cocaine injected into an animal remains in its tissues and in the cerebrospinal fluid and the rest is eliminated in the urine.

This form of administration demonstrates its highly stimulating effects on the cerebral cortex, a feature which is never observed in coca chewers who are on the contrary depressed subjects with an obvious psychomotor deficiency. It is also of interest that cocaine is found in the blood and the tissues and is eliminated in the urine.

We believe that when cocaine is ingested through the mouth, as in the case of coca leaf chewing, a very complex metabolic process takes place, as well as pharmacological actions of different kinds, due to the concurrence of a series of successive chemical and physiological phenomena.

According to the report of the Commission of Inquiry on the Coca Leaf [ 23] the coca addict chews on an average 50 grammes of coca leaf divided into three doses, which represents approximately 350 milligrammes of cocaine, slightly more than the figures given by Ciuffardi [ 8] . If that quantity of cocaine were completely absorbed and passed into the bloodstream, we should certainly find a display of cortical stimulation through this alkaloid, with all the pharmacological characteristics of cocaine administered parenterally, as we have just seen. The dose mentioned exceeds that generally used by cocaine addicts through the nose, and even the doses considered to be toxic; since neither cortical stimulation nor toxic effects are observed in the coca chewer let us consider what is likely to happen to the cocaine.

When the coca leaf is chewed, generally with the addition of an alkaline substance (tocra or llipta), it releases its alkaloids in the basic state and these, carried down by the saliva, follow the course of the gastro-intestinal tract. In this stage of cocaine absorption, a most important fact is observed, namely that cocaine, like all alkaloids, is probably salified in the plant with organic acids and when chewed should dissolve in the saliva, but this does not happen. In order to achieve that result the coca bolus has to be previously alkalinized by means of the various kinds of alkaline substances used by addicts in different parts of the country. Without such substances complete extraction is impossible and the chewer does not experience fully the desired effect. We studied this phenomenon in the laboratory, finding that weak alkaline solutions have a greater dissolvent effect on basic cocaine than water. Cruz Sánchez [ 9] arrived at the same conclusion and this justifies the addicts' practice of using alkaline substances.

Another important fact which we observed is that although alkaline solutions extract cocaine easily, this is only done by breaking up the cocaine. Hydrolysis of the alkaloid begins in the mouth, due to the action of the alkaline substance added to the coca leaf, and possibly as we shall see, to the action of the saliva itself.

Cocaine continues breaking up as it passes through the alimentary canal, as we confirmed in the laboratory, where we ascertained in vitro the action of the organic digestive juices on cocaine, in order to determine the degree to which they can break it up. Parra Garcia [ 30] proves that cocaine undergoes hydrolysis in the following proportions:

20.38% through the action of artificially obtained saliva.

5.48 % through the action of artificial gastric juice.

26.39 % through the action of natural pancreatic juice (in dogs).

33.39 % through the action of pancreatic juice and natural bile fin dogs).

8.55 % through the action of intestinal juice (in dogs).

71.71 % through the action of intestinal mucosa extract (in dogs).

Parra Garcia makes the important observation that it is in the intestinal canal, or rather in its wall, that cocaine undergoes the most intense hydrolysis; almost three quarters of the cocaine is broken up, a result coinciding with the Kohn-Abrest's conclusion [ 24] .

If it is remembered that all the digestive juices take part in the hydrolysis, although each to a different degree of intensity, it must be supposed that the amount of cocaine passing into the bloodstream is insignificant in relation to the amount entering the organism.

Continuing Parra Garcia's work, Cusquín Mendoza [ 12] studies the products of cocaine hydrolysis obtained in vitro by intestinal action of enzymes, and proves that cocaine undergoes hydrolysis when acted upon by an extract of a dog's intestinal mucosa. A chromatographic test made on the product reveals the presence of benzoyl-ecgonine.

We were unable to observe the action of the liver on the remainder of the cocaine which reaches it, but we presume that it is almost or entirely hydrolized when it passes through that organ, since Heim and Haas [ 20] have shown that it has a greater capacity for degrading esters than the kidney, brain and muscle.

Heim also demonstrates the existence in the liver of a cocainesterase which breaks down cocaine into benzoylecgonine; he does not mention the formation of ecgonine. Other writers also indicate benzoyl-ecgonine as the final product of cocaine metabolism. We ourselves consider ecgonine to be the final product, since it is found in the urine of animals subjected to experiments, and in that of the coca chewer, as was proved by Aguayo Sánchez [ 1] .

Cutipa Flores [ 11] has also undertaken the chromatographic study of cocaine metabolites, this time in the urine of rabbits to which cocaine has been administered intravenously and orally, the urine being collected within the following 32 hours. He finds excretion products between 6 and 20 hours afterwards when the cocaine is administered parenterally and between 8 and 24 hours afterwards when it is administered orally. Out of 50 mg. administered parenterally he recovers 19 mg. in the urine, and out of the same quantity administered orally he recovers only 2 mg. Although no quantitative determination of ecgonine was made, the results are very significant and indicate the disintegration of Cocaine when administered orally.

Although Zapata [ 37] described a suitable process for the identification and quantitative determination of cocaine in the blood and the urine, and we had various exact processes available for the determination of ecgonine we were unable to demonstrate either the absence of cocaine or the presence of ecgonine in the coca chewer's bloodstream. Nevertheless the results of studies which we mention below are significant and fully remedy such deficiences in our research, especially those obtained by Glick and Glaubach [ 16] who in 1942 made strenuous efforts to demonstrate the existence in the blood of experimental animals of cocainesterase, which through enzyme action breaks up cocaine into benzoyl-ecgonine and methanol.

Brünning [ 4] suggests research on corpses of persons infected with cocaine, in order to discover by means of Reinnecke's salt the ecgonine product of the breakup of the original alkaloid.

Glick and Glaubach [ 16] demonstrate that the different enzymes which hydrolize the esters of nitrogen alcohol vary within the same category.

Glick [ 15] suggests the term "azolesterase" for esterases acting on esters of nitrogen alcohols, which include cocainesterase.

Glick and Glaubach [ 16] find cocainesterase in the alpha and beta globulins of the blood. Ammon and Savelsberg [ 3] make a detailed study of rabbit serum and arrive at similar conclusions to those reached by Glick and Glaubach [ 16] . Some contain atropinesterase and cocainesterase, others only one of these, and some contain neither. These writers also believe that cocaine is broken up into benzoyl-ecgonine and methanol. Furthermore they state that they have not found cocainesterase in the serum of apparently normal persons.

Woods, McMahon and Seevers [ 35] show that cocainesterase is practically all metabolized in the body of the dog and that the amount excreted without change in the urine is very small. We presume that this enzyme is present in the serum of the apparently normal person, and in larger quantities in that of the coca addict, a presumption which was confirmed in the laboratory. During the research which we undertook to establish the spectrophotometric method of using the blood of non-addicts to which cocaine had been added, we obtained varying results ; at times we could determine the enzyme and at others we could not even identify it. At first, we attributed this fact to faults in the method of operation, but finally we reached the conclusion that it was due to the possible breaking up of the cocaine into a product which presents no absorption spectrum, perhaps ecgonine [ 21] .

Similarly a series of quantitative determinations in vitro, using dog's blood to which cocaine had been added, gave us progressively diminishing results, which indicated the presence of a substance, possibly diastatic, which caused hydrolysis of the cocaine.

Aguirre [ 2] shows that the addition of sodium fluoride, a diastatic inhibitor, prevents the disappearance of cocaine in samples of dog's blood. These results lead us to accept the existence of a cocainesterase in the blood serum, and also confirm our assumption that cocaine introduced directly into the bloodstream would in any case be affected by the diastases present in the blood and would be eliminated in appreciably smaller amounts in the urine. We therefore reached the conclusion that in the case of addicts, cocaine would reach the blood in very small quantities and therefore its metabolites must be sought not so much in the blood as in the organic liquids and tissues. Consequently, what should interest us chiefly are the pharmacological and toxic actions of these metabolites because they are what we find in the greastest proportion in the organism of addicts, for the probable biological reason that the production of diastases in the animal organism increases simultaneously with the presence of a greater number of substances on which they act.

Aguayo Sánchez [ 1] , in the most important contribution to this research, detects ecgonine in the urine of addicts by chromatographic analysis. In the first place he confirms the values given by Castañeda Pérez (6) for ecgonine: RF= 0.05. He establishes the presence of ecgonine as the sole excretary product of cocaine.

Lastly, Vega Godoy [ 34] concludes for the present this series of studies on the pharmacological action of ecgonine and arrives at the following conclusions:

Ecgonine modifies the degree of blood pressure producing slight hypotension, has no influence on the salivary and suderiferous glands, slightly reduces the rate of breathing, produces slight myosis without altering the pupillary reflex, has no effect on the contraction of the striated muscle, and produces moderate relaxation of the muscles of the small intestine in the rat, while maintaining the intensity of its peristaltic movements; the toxic dose of ecgonine is between 100 and 110 mg for a mouse weighing 25 to 30 g.


The results of this series of studies carried out at the Faculty of Pharmacy and Biochemistry under my direction, and of those of other writers, enable us to give a reasoned explanation of the metabolism of cocaine in the animal organism, and particularly in the organism of the coca leaf chewer, as follows:

  1. An average of 50 grammes of coca leaf chewed daily by the addict causes approximately 350 milligrammes of basic cocaine to be ingested into the organism corresponding to 235 milligrammes of ecgonine.

  2. After ingestion into the organism through the mouth, cocaine undergoes constant hydrolysis, first through the alkali by which it is invariably accompanied, then through the different digestive juices, saliva, gastric juice, pancreatic juice, bile and intestinal juice, giving rise first to benzoyl-ecgonine and finally to ecgonine.

  3. The original quantity of cocaine is considerably reduced at the moment of absorption together with the intestinal content; the remainder is totally converted into benzoyl-ecgonine and ecgonine in the liver.

  4. The blood may be supposed to pass through the suprahepatic vein from the liver into the bloodstream with traces of cocaine.

  5. The cocainesterase existing in the blood, presumably in greater proportion in coca addicts, no doubt produces the final hydrolysis of the cocaine residue.

  6. The renal elimination of the cocaine metabolite, ecgonine, begins six hours after ingestion and continues up to 20 hours afterwards.

  7. It is possible that in the addict the process of hydrolysis and elimination of cocaine products is more intense and rapid than in normal persons, for natural biological reasons.

  8. We have not ourselves investigated benzoyl-ecgonine in the urine but everything points to the fact that this metabo1ite does not exist in the urine or only in very small quantities. In our opinion ecgonine is the only final urinary metabolite into which cocaine is converted.

  9. The amount of cocaine circulating in the addict's organism is insignificant and the amount of ecgonine very appreciable.

  10. The preliminary pharmacological and toxicological study of ecgonine indicates among other effects slight arterial hypotension and a high degree of innocuity.

  11. It is quite possible that the addict may absorb directly through the buccal and gastric mucosa very small amounts of cocaine which are disintegrated by the cocainesterase in the blood, without any appreciable quantities remaining in the circulation or in the tissues.



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