2_Maurer-2006-Toxicokinetics of drugs of abuse

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Toxicokinetics of Drugs of Abuse: Current Knowledge
of the Isoenzymes Involved in the Human Metabolism
of Tetrahydrocannabinol, Cocaine, Heroin, Morphine,
and Codeine
Hans H. Maurer, Christoph Sauer, and Denis S. Theobald
Abstract: This review summarizes the major metabolic pathways
of the drugs of abuse, tetrahydrocannabinol, cocaine, heroin,
morphine, and codeine, in humans including the involvement of
isoenzymes. This knowledge may be important for predicting
their possible interactions with other xenobiotics, understanding
pharmaco-/toxicokinetic and pharmacogenetic variations, tox-
icological risk assessment, developing suitable toxicological
analysis procedures, and finally for understanding certain
pitfalls in drug testing. The detection times of these drugs and/
or their metabolites in biological samples are summarized and
the implications of the presented data on the possible inter-
actions of drugs of abuse with other xenobiotics, ie, inhibition or
induction of individual polymorphic and nonpolymorphic
isoenzymes, discussed.
Key Words: drugs of abuse, metabolism, toxicokinetics, cocaine,
codeine, heroin, morphine, tetrahydrocannabinol
(Ther Drug Monit 2006;28:447–453)
Individual variations in the pharmacological or toxico-logical responses to the same drug dose may be caused
by a variety of factors such as body mass, age, sex, kidney
and liver function, drug–drug (food–drug) interactions,
and genetic variability.1 Detailed knowledge of the
metabolism of drugs (of abuse) allows for the prediction
of possible interactions with other xenobiotics because of,
for example, inhibition or induction of individual meta-
bolic isoenzymes by poisons, drugs (of abuse), alcohol,
tobacco smoke or food ingredients. It is thus a
prerequisite for understanding pharmaco-/toxicokinetics,
pharmacogenetic variations, evidence-based case inter-
pretation, toxicological risk assessment, developing
toxicological analysis procedures, and understanding
pitfalls in drug testing.
Drug metabolism is largely determined by the
relevant genetic variants of metabolic enzymes or trans-
port proteins. The most important variants are the
following polymorphically expressed proteins: the cyto-
chrome P450 (CYP) isoenzymes CYP2C9, CYP2C19, and
CYP2D6, the alcohol dehydrogenase ADH2 and the
aldehyde dehydrogenase ALDH2, the phase II enzymes
uridine diphosphate glucuronyltransferases (UGT)
UGT1A1, thiopurin methyltransferases, arylamine N-
acetyl transferases NAT2 and glutathione S-transferases
GSTM1 and GSTT1, and finally transporters like P-
glycoprotein.1 Genetic variants of CYP have been
discovered because of the atypical clinical responses of
certain individuals to certain drugs, which could later be
attributed to a reduced ability of these individuals to
metabolize the respective drugs. At least 30 drugs have
subsequently been shown to be oxidized by CYP2D6,
including dextromethorphan, tricyclic antidepressants,
some neuroleptics, beta-blockers, and antiarrhythmic
agents such as perhexiline and flecainide, and drugs
of abuse including eg, codeine, dihydrocodeine, and
oxycodone.2 Also designer drugs like para-methoxyam-
phetamine,3 para-methoxymethamphetamine,4 or the
piperazines 1-(3-chlorophenyl)piperazine (mCPP),5 1-(4-
methoxyphenyl)piperazine,6 and 1-(3-trifluoromethylphe-
nyl)piperazine7 were shown to be predominantly or
exclusively metabolized by this enzyme. CYP2D6-
mediated metabolism of such drugs is known to be a
major source of pharmacokinetic variations or variations
in drug effects.
In the last few years, many studies have been
published regarding the impact of pharmacogenetic
variability, for example, on drug transport and meta-
bolism resulting in different pharmacokinetic behavior or
toxic risks.1,2,8–15 In addition, variations resulting from
interactions with other drugs of abuse, therapeutically
administered drugs, food ingredients and/or smoking and
the impact of supra-pharmacological doses on drug
disposition must be taken into consideration.16–21 For
assessment or prediction of all these variations, it is
important to know whether an individual has a reduced
or an increased turnover in these steps due to geneticCopyright r 2006 by Lippincott Williams & Wilkins
Received for publication January 23, 2006; accepted February 27, 2006.
From the Department of Experimental and Clinical Toxicology,
Institute of Experimental and Clinical Pharmacology and Toxico-
logy, University of Saarland, D–66421 Homburg (Saar), Germany.
Dedicated to Prof Dr Irving Sunshine at the occasion of his 90th
birthday.
Reprints: Prof Hans H. Maurer, PhD, Department of Experimental and
Clinical Toxicology, University of Saarland, D-66421 Homburg
(Saar), Germany (e-mail: hans.maurer@uniklinikum-saarland.de).
REVIEW ARTICLE
Ther Drug Monit � Volume 28, Number 3, June 2006 447
variations or drug/food interactions via enzyme inhibition
or induction. Furthermore, knowledge about the iso-
enzymes involved in the particular metabolic steps of all
used drugs is of great importance. Today, pharmaceutical
companies are required to provide such data for all new
drug entities introduced into the market. They are usually
published in review articles2,22 or drug information
handbooks or databases (eg, Refs. 23, 24). In contrast,
such data on illicit drugs of abuse are found in various
publications. Therefore, in the following pages, the main
metabolic steps and the isoenzymes involved therein will
be reviewed for delta9-tetrahydrocannabinol, cocaine,
heroin, morphine, and codeine. Data for amphetamines
and designer drugs of the ecstasy, the piperazine-, and the
pyrrolidinophenone-type are not included here, because
they have recently been reviewed elsewhere.25–29 Know-
ledge of the toxicokinetics of drugs of abuse is important
to find out which drug can be detected in which body
sample (urine, blood, saliva, sweat, hair, nails), via which
target analyte (parent drug or metabolite) and for how
long.30–32 In addition, this knowledge is needed to find
out whether a detected compound is formed by a licit
(eg, codeine) or an illicit drug (eg, heroin). Finally, for
pharmacological and/or toxicological interpretation of
the analytical results, pharmacokinetic calculations are
often used as a basis.33 However, kinetic data coming
either from controlled studies or from single case reports
may not reflect kinetic data in drug abuse situations and
must therefore be used very carefully.
METABOLISM OF TETRAHYDROCANNABINOL
Delta9-tetrahydrocannabinol (THC, also named
delta1-tetrahydrocannabinol according to the monoter-
penoid nomenclature), the primary hallucinogenic con-
stituent of Cannabis sativa, is subject to hepatic
metabolism primarily by hydroxylation (Fig. 1). The
primary metabolite 11-hydroxy-THC (HO-THC), which
is pharmacologically active, is formed by CYP2C9,34–37
and further oxidized, probably by alcohol dehydrogenase
or microsomal alcohol oxygenase, to the intermediate
aldehyde 11-oxo-THC followed by oxidation to 11-nor-9-
carboxy-THC (THC-COOH) catalyzed by a microsomal
aldehyde oxygenase, a member of the CYP2C subfam-
ily.35,38,39 After glucuronidation of the carboxy group,40
THC-COOH is excreted in urine and can be detected up
to 4 days after smoking 1 marijuana cigarette and up to 4
weeks after frequent use.30,31 In blood, THC levels increase
rapidly after smoking, peak before the end of smoking, and
quickly dissipate. Mean peak HO-THC levels are sub-
stantially lower than THC levels and occur immediately
after the end of smoking. THC-COOH levels increase
slowly and plateau for an extended period. The mean peak
time for THC-COOH is about 2 hours after smoking and a
correspondingly longer time course of detection can be
observed.41 THC-COOH glucuronide is present in blood at
considerably higher concentrations than the unconjugated
acid and is unstable to hydrolysis.42 This may cause
misinterpretation when using models for the prediction
of time of cannabis exposure.43
Further minor metabolic steps yieldseveral hydroxy
metabolites at C1’ to C5’ followed by beta-oxidation
to the corresponding carboxylic acids ((CH2)nCOOH),
37
2 diastereomeric 8-hydroxy metabolites followed by
dehydration,36,37 and an epoxide at C9-10 followed
by hydrolysis or glutathione conjugation.36 Formation
of 8-hydroxy-THC and the epoxide are catalyzed by
CYP3A4.36 Finally, several combinations of the meta-
bolic steps have been described.37
Given the high affinity of CYP2C9 for the hydro-
xylation of THC, the potential for an interaction was
evaluated between THC, HO-THC, or THC-COOH and
the CYP2C9 substrate phenytoin.34 Surprisingly, THC
increased the rate of phenytoin hydroxylation in human
liver microsomes and expressed CYP2C9 enzyme (Super-
somes). Similar increases in the rate of phenytoin meta-
bolism were observed with coincubation of HO-THC and
THC-COOH. These in vitro data suggest the potential for
FIGURE 1. Major metabolic pathways
of delta9-tetrahydrocannabinol in hu-
mans with the isoenzymes involved.
Maurer et al Ther Drug Monit � Volume 28, Number 3, June 2006
448 r 2006 Lippincott Williams & Wilkins
an interaction from the concomitant administration of
THC and phenytoin that could result in decreased
phenytoin concentrations in vivo and thus an increased
risk of epileptic seizures.34
In the context of the use of cannabis-based medicine
extracts for therapeutic purposes, a study was performed
in a double-blind and placebo-controlled cross-over
design in which each of 24 volunteers received an oral
dose of THC, of a cannabis extract containing THC and
cannabidiol (CBD) or placebo in weekly intervals.38
Despite the large variation of the kinetic data, evidence
emerged from the total of the results that CBD partially
inhibits the CYP2C9-catalyzed hydroxylation of THC to
HO-THC. The probability for this inhibition is particu-
larly high for oral intake because THC and CBD attain
relatively high concentrations in the liver and because of
the high first-pass metabolism of THC. However, the
effect of CBD seems to be small in comparison to the
variability caused by other factors. Therefore, a pharma-
cokinetic reason for the differences determined between
pure THC and cannabis extract is improbable at the doses
chosen in this study.
METABOLISM OF COCAINE
Cocaine, the main alkaloid of Erythroxylum coca,
is a powerful stimulant that is primarily metabolized
by the 3 esterases pseudocholinesterase, human carbo-
xylesterase-1 (hCE-1), and human carboxylesterase-2
(hCE-2).44–48 Figure 2 shows that cocaine is hydrolyzed
mainly by hCE-1 to benzoylecgonine, the primary
metabolite excreted in the urine, or by pseudocholinester-
ase and hCE-2 to ecgonine methyl ester. In the presence
of ethanol, hCE-1 catalyzes transesterification of cocaine
to cocaethylene, a toxic metabolite, that can be further
hydrolyzed by hCE-1 to benzoylecgonine or by hCE-2 to
ecgonine ethyl ester.44,45,47
The main metabolite benzoylecgonine could be
detected in urine for 2 to 3 days after an intranasal dose
of 100mg of cocaine, for 1.5 days after a single
intravenous dose of 20mg, and for 10 days after chronic
intravenous doses of 8 g/d.31 The detection time of
cocaine in blood is 4 to 6 hours after 20mg and 12 hours
after 100mg. In the serum of chronic users, benzoylecgo-
nine was detectable for 5 days on average.31 At this point,
it must be mentioned that cocaine may be enzymatically
degraded in blood samples during transport and storage,
which can be avoided by the use of blood sampling
devices containing the cholinesterase inhibitor sodium
fluoride.49
The first step in the oxidative metabolism of cocaine
is N-demethylation to pharmacologically active norco-
caine catalyzed by 2 alternate pathways, one involving
only CYP3A450 and the other requiring both CYP and
flavin-containing monooxygenase . In the first pathway,
cocaine was directly N-demethylated to norcocaine by
CYP and the second route was found to be a 2-step
reaction involving cocaine N-oxide as an intermediate. In
this pathway, cocaine is first oxidized to cocaine N-oxide
by flavin-containing monooxygenase, followed by a CYP-
catalyzed N-demethylation to norcocaine.51 Norcocaine is
further metabolized by N–hydroxylation at least partly
catalyzed by several CYP subfamilies including 1A, 2A,
3A and possibly 2B.52 In addition, aromatic m- and p-
hydroxylation of cocaine partly followed by hydrolysis to
the corresponding hydroxy benzoylecgonine isomers
(minor pathways not shown in Fig. 2).53,54 Unfortunately,
the involved isoenzymes are not yet identified. Again, in
the presence of ethanol, hCE-1 catalyzes transesterifica-
tion of norcocaine to norcocaethylene that can be further
hydrolyzed by hCE-1 to benzoylnorecgonine.44,45,47
Crack is cocaine that has been processed from
cocaine hydrochloride to a free base for smoking. When
cocaine is smoked, a pyrolytic product, methylecgonidine
(anhydroecgonine methylester), is also consumed with the
cocaine. The amount of methylecgonidine formed
depends on the pyrolytic conditions and composition of
the illicit cocaine. Besides cocaine and its metabolites,
FIGURE 2. Major metabolic pathways
of cocaine in humans with the iso-
enzymes involved.
Ther Drug Monit � Volume 28, Number 3, June 2006 Toxicokinetics of Drugs of Abuse
r 2006 Lippincott Williams & Wilkins 449
3 metabolites of methylecgonidine could be identified:
ecgonidine (anhydroecgonine), ethyl ecgonidine (anhy-
droecgonine ethyl ester) and nor-ecgonidine (nor-
anhydroecgonine).54,55 Unfortunately, the isoenzymes
involved in the metabolism of methylecgonidine are not
yet identified.
More recently, the activity of several human
cholinesterase variants with cocaine has been examined.56
One atypical cholinesterase had 10-fold lower binding
efficiency for cocaine and 10-fold lower catalytic effi-
ciency. Although this evidence suggests the possibility
that individual responses to cocaine may be mediated in
part by greater or lesser metabolic capacity, genetically
determined variations in cholinesterase activity, or in
activity of the carboxylesterase, have not been investi-
gated in persons with addictive diseases.48
METABOLISM OF MORPHINE AND HEROIN
Morphine is the main alkaloid of Papaver somnifer-
um and is used therapeutically as a potent analgesic
although its 3,6-diacetyl derivative heroin is one of the
most dangerous drugs of abuse. The oral bioavailability
of heroin is poor only due to complete first-pass
metabolism by hepatic and extrahepatic factors.48
It exerts its effects only after metabolism to 6-monoace-
tylmorphine and morphine catalyzed in the liver by hCE-1
and hCE-2, in the serum by pseudocholinesterase, and also
nonenzymatically in the serum (Fig. 3). The catalytic
efficiency for both hydrolysis steps is substantially greater
for hCE-2 than for the other esterases.45,46,48,57
Morphine administered as a drug or formed
metabolically from heroin is mainly metabolized by
UGT to the inactive metabolite morphine-3-glucuronide
(M3G) and, to a lesser extent, to morphine-6-glucuronide
(M6G),48 that has equivalent analgesic effects to mor-
phine and an improved side effect profile with a reduced
tendency to cause nausea, vomiting, sedation and
respiratory depression.58 UGT2B7 is the major enzyme
involved in morphine 3- and 6-glucuronidation, but 1A1,
1A3, 1A6, 1A8, 1A9, 1A10 also more or less contribute to
M3G formation.59 Finally, morphine is N-demethylated
to normorphine by hepatic CYP3A4 and to a lesser extent
by CYP2C8.60 Today, all major heroin and morphine
metabolites can be monitored in urine and blood.61,62
The detection time of morphine in blood is 20 hours after
intravenous administration of 12 or 20mg heroin in a
subject.63 After being smoked, the detection time for
10.5mg of heroin varied between 22 minutes and
2 hours.63 In the blood of chronic users, total morphine
was detectable for 29.2 hours on average and free
morphine for 14.4 hours.64 After administration of 3 to
7 or 10.5 to 13.9mg heroin intravenously, 6-acetylmor-
phine was detectablein urine up to 5.1 hours (median 2.3)
and 2.3 to 11.2 hours (median 4.5), respectively, by
GC-MS with a cutoff of 10 ng/mL, whereas total
morphine was detectable in urine for 7.4 to 31.9 hours
(median 15.7) and 10.7 to 53.5 hours (median 34.4),
respectively, by GC-MS with a cutoff of 300 ng/mL.65
A recent study of 5 subjects with Gilbert syndrome,
characterized by impaired glucuronidation due to a
polymorphism in the gene encoding UGT1A1, did not
show altered morphine clearance or difference in the
plasma concentration versus time curves for M6G or
M3G compared with controls.66 The discussion on the
effect of UGT2B7 polymorphisms on M6G and M3G
formation and clearance is controversial.11,48
METABOLISM OF CODEINE
Codeine (3-methylmorphine) is a minor alkaloid of
Papaver somniferum. Synthesized from morphine, it is
used therapeutically primarily as a potent antitussive, but
also misused, for example, by opiate addicts because it is
metabolized to morphine which is further metabolized by
N-demethylation and glucuronidation as described earlier
FIGURE 3. Major metabolic pathways
of heroin and morphine in humans with
the isoenzymes involved.
Maurer et al Ther Drug Monit � Volume 28, Number 3, June 2006
450 r 2006 Lippincott Williams & Wilkins
(Fig. 4). The O-dealkylation to morphine is catalyzed by
polymorphically expressed CYP2D6 as is also the case for
its congeners dihydrocodeine, ethylmorphine, hydroco-
done, or oxocodone.11,12,48 Some variants of the CYP2D6
gene increase metabolism of these drugs to their more
potent metabolites, whereas others decrease metabolism,
which may influence the analgesic potency and abuse
liability.67–69 However, their clinical relevance, though
controvertial, is being discussed.48
In addition, codeine is N-demethylated by
CYP3A470,71 and conjugated equally by UGT2B4 and
UGT2B7 to codeine-6-glucuronide so that UGT2B7
polymorphism plays no significant role in this step.72
CONCLUSIONS
The knowledge of major metabolic pathways of
drugs of abuse in humans and the isoenzymes involved
therein may be important to predict possible interactions
with other xenobiotics, to understand pharmaco-/toxico-
kinetics and pharmacogenetic variations, to understand
toxic risks, to develop suitable toxicological analysis
procedures, and finally to understand pitfalls in drug
testing.
ACKNOWLEDGMENTS
The authors would like to thank Andreas H. Ewald
and Frank T. Peters for their help.
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