Compilation: Metabolism of various psychoactives

[Paracelsus]

This thread is supposed to become an informational resource on the metabolism of specific psychoactive drugs.

There will be a short entry for each drug. Each entry should include:

- basic information about the drug's metabolism: through what pathways is it metabolized? To what extent (minor/major pathways)? Into what metabolites? What is the activity of these metabolites (are they inactive, similar to the prodrug or completely different)?
- how do inducers/inhibitors of the respective enzyme(s) affect the drug's range of effects, potency, and duration?
- are there any known genetic variations in the activity of the respective enzyme(s) that may alter drug pharmacology and toxicology? (deficiencies, duplicated alleles, poor/intermediate/extensive/ultrarapid metabolizers, etc.)
- how does the drug affect the enzymes responsible for its metabolism (does the drug inhibit or inactivate the enzyme(s)? If so, to what extent? Does the drug induce the enzyme(s)? If so, to what extent?
- references for the claims made

All this will of course be hard to comprehend for the average user, but the reason why I created this thread is to provide concise quick reference (to provide an alternative to endless digging through PubMed and the file archive) and provide information to members who may write articles about the respective drugs (because in the articles, all this information has to be made more understandable and detailed).

I will continue working on this list but thought that I should post it so maybe other members could help. Red bold text means that there is something incomplete. The following are drugs which are mainly metabolized by cytochrome P450. Information on drugs metabolized by other metabolic pathways (MAO, etc) is, of course, very welcome.


Metabolism of various psychoactives
Prediction of drug interactions


Codeine
Very weak μ-opioid agonist. Metabolized by CYP2D6 into morphine (potent μ-opioid agonist), by CYP3A4 into norcodeine (inactive), and by UGT2B7 into codeine-6-glucuronide (inactive).
CYP2D6 poor metabolizers can not metabolize codeine into morphine, which is why codeine does not have significant opioid-like effects in these individuals. A significant reduction in opioid-like effects is expected if CYP2D6 inhibitors are used in combination with codeine. In CYP2D6 ultrarapid metabolizers, codeine has increased opioid-like effects, which can result in life-threatening overdose, for example if a codeine-naïve ultrarapid metabolizer consumes a high dose.
CYP3A4 inhibitors reduce the rate of N-demethylation of codeine and morphine, thus potentiating the effects of codeine. The opposite is expected from CYP3A4 inducers.
The effect of UGT2B7 inducers/inhibitors is unclear. Codeine-6-glucuronide may be metabolized to active morphine-6-glucuronide. See also morphine.
At high recreational doses, codeine has a ceiling effect (higher doses don't cause more effects). This is generally explained by saturation of CYP2D6, which suggests that codeine (even in lower recreational doses) is a competitive CYP2D6 inhibitor. [REFERENCE]
Poulsen et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effects and side effects (abstract). Eur J Clin Pharmacol 1996;51(3-4):289-95.
Gasche et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004;351:1827-31.
Kirchheiner et al. Pharmacokinetics of codeine and its metabolite morphine in ultrarapid metabolizers due to CYP2D6 duplication (abstract). Pharmacogenomics J 2007 Aug;7(4):257-65.
Eckhardt et al. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation (abstract). Pain 1998 May;76(1-2):27-33.

Tramadol (Ultram)
Serotonin-norepinephrine reuptake inhibitor and a very weak μ-opioid agonist. Metabolized by CYP2D6 into O-desmethyltramadol (more potent μ-opioid agonist) and by CYP3A4 into N-desmethyltramadol and N,N-didesmethyltramadol (both inactive).
CYP3A4 inhibitors reduce the conversion of tramadol into inactive N-demethylated metabolites, increasing its availability to the CYP2D6 pathway, thus potentiating its effects (grapefruit is often used for this purpose). CYP3A4 induction is expected to lower potency.
CYP2D6 poor metabolizers experience less analgesia and no opioid-like effects from tramadol. The same applies if CYP2D6 inhibitors are used. CYP2D6 inducers are expected to potentiate tramadol. Tramadol is expected to have increased opioid-like effects in CYP2D6 ultrarapid metabolizers, which may result in life-threatening overdose. The adverse effects of tramadol negatively correlate with CYP2D6 activity (CYP2D6 ultrarapid metabolizers experience the least adverse effects, CYP2D6 poor metabolizers experience the most).
Significant competitive inhibition of CYP3A or CYP2D6?
Other pathways (conjugation, etc) See ref #2
Gan SH et al. Impact of CYP2D6 polymorphism on tramadol pharmacokinetics and pharmcodynamics (abstract). Mol Diagn Ther 2007;11(3):171-81.
Grond & Sablotzki. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004;43(13):879-923.
Poulsen et al. The hypoalgesic effect of tramadol in relation to CYP2D6 (abstract). Clin Pharmacol Ther 1996 Dec;60(6):636-44.

Morphine
Potent μ-opioid agonist. Metabolized by UGT2B7 into (active) morphine-6-glucuronide (M6G), (inactive) morphine-3-glucuronide (M3G), and (inactive) morphine-3,6-diglucuronide (M36DG), and by CYP3A4 into (active) normorphine (minor pathway).
No expected significant interactions involving the CYP450 system.
UGT2B7 inhibitors decrease the formation of morphine glucuronides, but their effects on the psychological and physiological effects of morphine are not yet determined.
Coffman et al. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 1997;25(1):1-4.
Projean et al. Identification of CYP3A4 and CYP2C8 as the major cytochrome P450s responsible for morphine N-demethylation in human liver microsomes (abstract). Xenobiotica 2003 Aug;33(8):841-54.
Rios & Tephly. Inhibition and active sites of UDP-Glucuronosyltransferases 2B7 and 1A1. Drug Metab Dispos 2002 Dec;30(12):1364-7.

Tilidine (Valoron, Valtran)
Very weak μ-opioid agonist. Metabolized by CYP3A4 into nortilidine and bisnortilidine (both more potenct μ-opioid agonists).
CYP3A4 inducers are expected to potentiate the effects of tilidine. The opposite is expected from CYP3A4 inhibitors.
Possibly significant competitive CYP3A inhibitor
Seiler et a;. Pharmacokinetics of tilidine and naloxone in patients with severe hepatic impairment. Arzneimittelforschung 2007;57(2):106-11.
Thierry et al. Actions of tilidine and nortilidine on cloned opioid receptors. Eur J Pharmacol 2005 Jan 4;506(3):205-8.

Hydrocodone (Vicodin, Lortab)
μ-opioid agonist. Metabolized by CYP2D6 into (more potent μ-opioid agonist) hydromorphone and by CYP3A4 into (inactive) norhydrocodone.
CYP3A4 inhibitors are expected to potentiate hydrocodone by inhibiting its conversion to norhydrocodone. The opposite is expected from CYP3A4 inducers.
Although its metabolite hydromorphone is significantly more potent than hydrocodone, CYP2D6 activity does not have any significant influence on the effects of hydrocodone.
Otton et al. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone (abstract). Clin Pharmacol Ther 1993 Nov;54(5):463-72.
Hutchinson et al. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes (abstract). Br J Clin Pharmacol 2004 Mar;57(3):287-97.
Kaplan et al. Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther 1997 Apr;281(1):103-8.

Oxycodone (Percocet, OxyContin)
μ-opioid agonist. Metabolized by CYP2D6 into (more potent μ-opioid agonist) oxymorphone and by CYP3A4 into (inactive) noroxycodone.
CYP3A4 inhibitors are expected to potentiate oxycodone by inhibiting its conversion to noroxycodone. The opposite is expected from CYP3A4 inducers.
Although its metabolite oxymorphone is significantly more potent than oxycodone, CYP2D6 activity does not have any significant influence on the effects of oxycodone.
Heiskanen et al. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone (abstract). Clin Pharmacol Ther 1998 Dec;64(6):603-11.
Lalovic et al. Pharmacokinetics and pharmacodynamics of oxycodone in healthy human subjects: role of circulating active metabolites (abstract). Clin Pharmacol Ther 2006 May;79(5):461-79.

Alfentanil (Alfenta)
Highly potent μ-opioid agonist. Metabolized by CYP3A into noralfentanil and N-phenylpropionamide.
Alfentanil potency negatively correlates with CYP3A activity. This suggests that aforementioned metabolites are either inactive or of lower potency, that CYP3A inhibitors may potentiate alfentanil, and that CYP3A inducers may reduce its efficacy.
Klees et al. Metabolism of alfentanil by cytochrome P4503A (CYP3A) enzymes. Drug Metab Dispos 2005 Mar;33(3):303-11.
Kharasch et al. Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis (abstract). Clin Pharmacol Ther 2004 Nov;76(5):452-66.

Levo-alpha-acetylmethadol, LAAM
Long-acting μ-opioid agonist. Metabolized by CYP3A into (more potent and longer-lasting) norLAAM and dinorLAAM.
The effects of induction and inhibition of CYP3A on the effects of LAAM is scarcely documented. It was shown that rifampicin (a CYP3A inducer) does not potentiate LAAM, but this may be caused by the fact that rifampicin also induces CYP2C9 and CYP2D6, which may play a (yet undetermined) role in the metabolism of LAAM and its active metabolites.
Possibly significant competitive CYP3A inhibitor
Kharasch et al. Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol: importance of clinical investigations to validate in vitro drug metabolism studies. Clin Pharmacokinet 2005;44(7):731-51.

Pethidine AKA meperidine
μ-opioid agonist, local anaesthetic. N-demethylated by CYP2B6 and CYP3A4 into norpethidine (normeperidine), which is less active as an analgesic but is a potent neurotoxin (causes seizures). The risk of seizures is much increased in users with renal failure (norpethidine builds up), but seizures have been reported in healthy patients when pethidine was administered chronically.
CYP3A4 inducers (rifampicin, etc) are likely to increase the likelyhood of seizures. CYP3A4 inhibitors are expected to potentiate pethidine analgesia and decrease the risk of seizures, although this has not been verified.
Interesting & possibly useful bit of information: dextromethorphan (but not its metabolite dextrorphan) potentiate norpethidine-caused seizures in rats.
Ramírez et al. CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metab Dispos 2004;32(9):930-6.
Hassan et al. Successful treatment of normeperidine neurotoxicity by hemodialysis (abstract). Am J Kidney Dis 2000 Jan;35(1):146-9.
Jiraki K. Lethal effects of normeperidine (abstract). Am J Forensic Med Pathol 1992 Mar;13(1):42-3.
Marinella MA. Meperidine-induced generalized seizures with normal renal function (abstract). South Med J 1997 May;90(5):556-8.
McHugh GJ. Norpethidine accumulation and generalized seizure during pethidine patient-controlled analgesia (abstract). Anaesth Intensive Care 1999 Jun;27(3):289-91.
Kussman BD, Sethna NF. Pethidine-associated seizure in a healthy adolescent receiving pethidine for postoperative pain control (abstract). Paediatr Anaesth 1998;8(4):349-52.
Plummer et al. Interaction between dextromethorphan and norpethidine in rats (abstract). Eur J Pain 1997;1(3):191-6.

Ketamine (Ketalar, Ketanest)
Active per se (NMDA antagonist). Metabolized by CYP3A4 into (active) norketamine.
The effect of CYP3A4 inducers and inhibitors on the effects of ketamine is unclear, as the pharmacological effects of norketamine are similar to those of ketamine. Anecdotal reports indicate that grapefruit juice (a CYP3A4 inhibitor) may enhance the subjective effects of ketamine.
Dehydronorketamine
Hijazi & Boulieu. Contribution of CYP3A4, CYP2B6, and CYP2C9 isoforms to N-demethylation of ketamine in human liver microsomes. Drug Metab Dispos 2002 Jul;30(7):853-8.
Norketamine reference

Dextromethorphan, DXM
σ1 agonist. Metabolized by CYP2D6 into dextrorphan (NMDA antagonist) and by CYP3A4 into 3-methoxymorphinan (inactive).
CYP3A4 inhibitors reduce the conversion of dextromethorphan into 3-methoxymorphinan and of dextrorphan into 3-hydroxymorphinan (inactive), which potentiates its effects (grapefruit juice is often used for this reason). CYP3A4 inducers are expected to reduce potency.
CYP2D6 poor metabolizers show significant reduction in the conversion of dextromethorphan to dextrorphan, which in therapeutic use may cause drowsiness and in recreational use significantly potentiates DXM and greatly lengthens the experience. The same applies if CYP2D6 inhibitors are used.
The antitussive effects are believed to be caused by dextromethorphan per se. CYP2D6 inhibitors potentiate antitussive effects.
Most likely potent competitive CYP2D6 inhibitor (recreational doses only)
Abdul Manap et al. The antitussive effect of dextromethorphan in relation to CYP2D6 activity (abstract). Br J Clin Pharmacol 1999 Sep;48(3):382-7.
Zawertailo et al. Psychotropic effects of dextromethorphan are altered by the CYP2D6 polymorphism: a pilot study. J Clin Psychopharmacol 1998 Aug;18(4):332-7.
Di Marco MP et al. The effect of grapefruit juice on the pharmacokinetics of dextromethorphan: the role of gut CYP3A and P-glycoprotein. Life Sci 2002 Jul 26;71(10):1149-60.

MDMA, Ecstasy
Demethylenated into 3,4-dihydroxymethamphetamine (N-methyl-α-methyldopamine) by CYP2D6 (also CYP1A2 & CYP3A4 to a minor extent). The role of this metabolite in the subjective and physiological effects is not yet well determined. To a minor extent, MDMA is also N-demethylated to MDA (active) by CYP1A2 and CYP2B6.
CYP2D6 inhibitors may prolong effects, although data is very limited (one case report). However, it should be noted that the most commonly used potent CYP2D6 inhibitors are also SSRIs which prevent MDMA from exerting its effects.
MDMA is a CYP2D6 inactivator (in vitro). Most CYP2D6 is inactivated within 1 hour after administration. "[R]eturn to a basal level of CYP2D6 could take at least 10 days."
Segura et al. Contribution of cytochrome P450 2D6 to 3,4-methylenedioxymethamphetamine disposition in humans: use of paroxetine as a metabolic inhibitor probe (abstract). Clin Pharmacokinet 2005;44(6):649-60.
de la Torre et al. Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Ther Drug Monit 2004 Apr;26(2):137-44.
Harrington et al. Life-threatening interaction between HIV-1 protease inhibitors and the illicit drugs MDMA and gamma-hydroxybutyrate. Arch Intern Med 1999 Oct 11;159(18):2221-4.
Heydari et al. Mechanism-based inactivation of CYP2D6 by methylenedioxymethamphetamine. Drug Metab Dispos 2004 Nov;32(11):1213-7.
Yang et al. Implications of mechanism-based inhibition of CYP2D6 for the pharmacokinetics and toxicity of MDMA (abstract). J Psychopharmacol 2006 Nov;20(6):842-9.
Kraemer & Maurer. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Therapeutic Drug Monitoring 2002;24:277-89.

Methamphetamine
Hydroxylated into parahydroxymethamphetamine (unknown activity, most likely similar to PHA – see PMA entry) by CYP2D6.
Induces CYP2D2 and CYP3A1/2 in rats. May have the same effects on human equivalents (CYP2D6 and CYP3A4, respectively), although this is unproven (and unlikely in the case of CYP2D6).
Dostalek et al. Effect of methamphetamine on the pharmacokinetics of dextromethorphan and midazolam in rats (abstract). Eur J Drug Metab Pharmacokinet 2005 Jul-Sep;30(3):195-201.
Kraemer & Maurer. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Therapeutic Drug Monitoring 2002;24:277-89.

PMA, paramethoxyamphetamine
Serotonin releaser & reuptake inhibitor, dopamine reuptake inhibitor. O-demethylated by CYP2D6 into parahydroxyamphetamine (alpha-methyltyramine), which acts similarly as the parent compound. The role of this metabolite in the toxicity of PMA is not determined yet.
Wu et al. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol 1997 Jun 1;53(11):1605-12.
Kaminskas et al. The contribution of the metabolite p-hydroxyamphetamine to the central actions of p-methoxyamphetamine. Psychopharmacology 2002;160:155-60.

MMDA-2, 2-methoxy-4,5-methylenedioxyamphetamine
Potent competitive CYP2D6 inhibitor (in vitro).
Wu et al. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol 1997 Jun 1;53(11):1605-12.

Amphetamine
4-hydroxylated into parahydroxyamphetamine (pharmacologically similar to PMA) via CYP2D6 (in the rat), oxidized by CYP2C into phenylacetone (in the rabbit).
Moody et al. Quinidine inhibits in vivo metabolism of amphetamine in rats: impact upon correlation between GC/MS and immunoassay findings in rat urine (abstract). Journal of Analytical Toxicology 1990 Sep-Oct;14(5):311-7.
Shiiyama et al. Major role of CYP2C isozymes in deamination of amphetamine and benzphetamine: evidence for the quinidine-specific inhibition of the reactions catalyzed by rabbit enzyme (abstract). Xenobiotica 1997 Apr;27(4):379-87.

MDA, 3,4-methylenedioxyamphetamine
Demethylenated by CYP2D6 (in vitro).
Potent competitive CYP2D6 inhibitor (in vitro).
Wu et al. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol 1997 Jun 1;53(11):1605-12.
Kraemer & Maurer. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Therapeutic Drug Monitoring 2002;24:277-89.

MMDA, 3-methoxy-4,5-methylenedioxyamphetamine
Demethylenated by CYP2D6 (in vitro).
Potent competitive CYP2D6 inhibitor (in vitro).
Wu et al. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol 1997 Jun 1;53(11):1605-12.
Kraemer & Maurer. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Therapeutic Drug Monitoring 2002;24:277-89.

MBDB, 1-(1,3-benzodioxol-5-yl)-N-methylbutan-2-amine
N-demethylated into (active, similar) BDB by CYP1A2, CYP2B6 and CYP3A4.
Potent competitive CYP2D6 inhibitor (in vitro). Demethylenated (in vitro) by CYP2D6 (also by CYP1A2 & CYP3A4 to a minor extent).
Wu et al. Interactions of amphetamine analogs with human liver CYP2D6. Biochem Pharmacol 1997 Jun 1;53(11):1605-12.
Kraemer & Maurer. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Therapeutic Drug Monitoring 2002;24:277-89.

MDE, MDEA, Eve, 3,4-methylenedioxyethylamphetamine
N-deethylated into MDA (active) by CYP3A4 & CYP2B6 (in vitro). Demethylenated by CYP2D6 (in vitro).
Kraemer & Maurer. Toxicokinetics of amphetamines: metabolism and toxicokinetic data of designer drugs, amphetamine, methamphetamine, and their N-alkyl derivatives. Therapeutic Drug Monitoring 2002;24:277-89.

Carisoprodol (Soma)
N-deisopropylated to meprobamate (a tranquilizer and muscle relaxant) by CYP2C19.
Although it is believed that its conversion to meprobamate is responsible for the abuse potential of carisoprodol, its effects were found not to significantly differ between extensive and intermediate CYP2C19 metabolizers.
Possible competitive CYP2C19 inhibitor.
Dalén et al. Formation of meprobamate from carisoprodol is catalyzed by CYP2C19. Pharmacogenetics 1996 Oct;6(5):387-94.
Bramness et al. Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects? Pharmacogenetics 2003 Jul;13(7):383-8.
Bramness et al. The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects. Eur J Clin Pharmacol 2005 Aug;61(7):499-506.

[Paracelsus]

Bump: added some info to some already existing entries (codeine, morphine, MDMA) + created new entries - various amphetamines & carisoprodol.

Next up: more opioids, possibly benzos.

[Pino]

Acetone:

2-Propanol (minor) and intermediary metabolites (largely excreted unchanged at higher concentrations)
Endogenous compound produced in large amounts in diabetic or fasting ketoacidosis; also the major metabolite of 2-propanol in man (Kawai et al. 1990).

Acetonitrile
Inorganic cyanide (at least 12 per cent) thence to thiocyanate exposure.
Cyanide/thiocyanate may accumulate during chronic

Benzene

Phenol (51-87 per cent), catechol (6 per cent), hydroquinone (2 per cent), trans,trans-muconic acid.
Excreted in urine as sulphate and glucuronide conjugates. Urinary phenol excretion has been used to indicate exposure but is variable and subject to interference.

Bromomethane

Inorganic bromide (and others?)
Serum bromide has been used to monitor exposure, although the concentrations associated with toxicity are much lower than when inorgani bromide is given orally.

Butanone

3-Hydroxybutanone (0.1 per cent)
3-Hydroxybutanone excreted in urine. Most of an absorbed dose of butanone excreted unchanged in exhaled air.

Carbon tetrachlorid

Chloroform, carbon dioxide, hexachloroethane and others
Trichloromethyl free radical (reactive intermediate) probably responsible for hepatorenal toxicity.

Chloroform

Carbon dioxide (ca. 50 per cent), diglutathionyl dithiocarbonate
Phosgene (reactive intermediate) depletes glutathione and is probably responsible for hepatorenal toxicity.

Cyclohexanone

Cyclohexanol (ca. 50 per cent)
Cyclohexanol excreted in urine largely as glucuronide
(Sakata et al. 1989).

Dichloromethane

Carbon monoxide (ca. 50
per cent)
Carbon monoxide half-life 13 hours (breathing air, atmospheric pressure). Blood carboxyhaemoglobin measurement useful indicator of chronic exposure.

Dimethylsulphoxide

Dimethylsulphide (3 per cent), dimethylsulphone (18-22 per cent) excreted in exhaled air.
After oral/dermal administration, dimethylsulphide and dimethylsulphone in urine.

Dioxane

Beta-hydroxyethoxyacetic acid (HEAA).
HEAA excreted in urine.

Enflurane

Difluoromethoxydifluoroacetic acid (>2.5 per cent), inorganic fluoride.

Ethyl acetate

Ethanol, acetic acid
Rapid reaction catalysed by plasma esterases.

Ethylbenzene

Methylphenylcarbinol (5 per cent), mandelic acid (64 per cent), phenylglyoxylic acid (25 per cent)
Methylphenylcarbinol excreted in urine as conjugate, others as free acids. Mandelic acid excretion has been used to monitor ethylbenzene exposure.

Halothane

Chlorotrifluoroethane, chlorodifluoroethylene, trifluoroacetic acid, inorganic bromide and others.
The formation of reactive metabolites may be important in the aetiology of the hepatotoxicity ("halothane hepatitis") which may occur in patients exposed to halothane.

Hexane

2-Hexanol, 2-hexanone, 2,5-hexanedione

2-Hexanol excreted in urine as glucuronide. 2,5-
Hexanedione thought to cause neurotoxicity. Methyl butyl
ketone also neurotoxic and also metabolised to 2,5-
hexanedione.

Isobutane

2-Methyl-2-propanol (<1 per cent?) -

Isobutyl nitrite

2-Methyl-1-propanol (99 per cent), inorganic nitrite.
Parent compound not detectable in blood. Blood methaemoglobin can be used to monitor exposure.

Isopentyl nitrite

3-Methyl-1-butanol (99 per cent),inorganic nitrite.
Parent compound not detectable in blood. Blood
methaemoglobin can be used to monitor exposure.

Methanol

Formaldehyde (up to 60 per cent), formic acid.
Urinary formic acid excretion has been advocated for monitoring methanol exposure.

Propane

2-Propanol, acetone (<1 per cent?)

2-Propanol

Acetone (80-90 per cent)
2-Propanol half-life ± 2 hours, acetone half-life ± 22 hours.

Styrene

Mandelic acid (85 per cent) and phenylglyoxylic acid (10 per cent)
Urinary mandelic acid excretion indicates exposure. Ethanol inhibits mandelic acid excretion (Wilson et al. 1983).

Tetrachloroethylene

Trichloroacetic acid (<3 per cent).
Urinary trichloroacetic acid excretion serves only as
qualitative index of exposure.

Toluene

Benzoic acid (80 per cent) and o-, m- and p-cresol (1 per cent).
Benzoic acid largely conjugated with glycine giving hippuric acid which is excreted in urine (half-life 2-3 hours). Not ideal index of exposure since there are other (dietary) sources of benzoic acid.

1,1,1-Trichloroethane

2,2,2-Trichloroethanol (2 per cent), trichloroacetic acid (0.5 per cent)
Urinary metabolites serve as qualitative index of exposure only (compare tetrachloroethylene).

Trichloroethylene

2,2,2-Trichloroethanol (45 percent), trichloroacetic acid (32 per cent).
Trichloroethanol (glucuronide) and trichloroacetic acid excreted in urine (half-lives ca. 12 and 100 hours). Trichloroacetic acid excretion can indicate exposure.

Xylenes

Methylbenzoic acids (95 percent) and xylenols (2 per cent).
Methylbenzoic acids conjugated with glycine and urinary methylhippuric acid excretion used as index of exposure - no dietary sources of methylbenzoates.

Reference: Volatile substance abuse

[psyche]

This is most excellent info. Someone give rep for this because I should spread rep around before giving it again to paracelcus. Didn't know there was a group of people that have faster version of CYP2D6.

[Politicalchalk]

LAAM

THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol. 297, Issue 1, 410-422, April 2001

Metabolism of levo--Acetylmethadol (LAAM) by Human Liver Cytochrome P450: Involvement of CYP3A4 Characterized by Atypical Kinetics with Two Binding Sites

Yutaka Oda and Evan D. Kharasch
Departments of Anesthesiology and Medicinal Chemistry, University of Washington, and the Puget Sound Veterans Affairs Medical Center, Seattle, Washington (E.D.K.); and Department of Anesthesiology, Osaka City University Medical School, Osaka, Japan (Y.O.)
levo--Acetylmethadol (LAAM) is a long-acting opioid agonist prodrug used for preventing opiate withdrawal. LAAM undergoes bioactivation via sequential N-demethylation to nor-LAAM and dinor-LAAM, which are more potent and longer-acting than LAAM. This study examined LAAM and nor-LAAM metabolism using human liver microsomes, cDNA-expressed CYP, CYP isoform-selective chemical inhibitors, and monoclonal antibody to determine kinetic parameters for predicting in vivo drug interactions, involvement of constitutive CYP isoforms, and mechanistic aspects of sequential N-demethylation. N-Demethylation of LAAM and nor-LAAM by human liver microsomes exhibited biphasic Eadie-Hofstee plots. Using a dual-enzyme Michaelis-Menten model, Km values were 19 and 600 µM for nor-LAAM and 4 and 450 µM for dinor-LAAM formation, respectively. LAAM and nor-LAAM metabolism was inhibited by the CYP3A4-selective inhibitors troleandomycin, erythromycin, ketoconazole, and midazolam. Of the cDNA-expressed isoforms examined, CYP2B6 and 3A4 had the highest activity toward LAAM and nor-LAAM at both low (2 µM) and high (250 µM) substrate concentrations. N-Demethylation of LAAM and nor-LAAM by expressed CYP3A4 was unusual, with hyperbolic velocity curves and Eadie-Hofstee plots and without evidence of positive cooperativity. Using a two-site model, Km values were 6 and 0.2 µM, 1250 and 530 µM, respectively. Monoclonal antibody against CYP2B6 inhibited CYP2B6-catalyzed but not microsomal LAAM or nor-LAAM metabolism, whereas troleandomycin inhibited metabolism in all microsomes studied. The ratio [dinor-LAAM/(nor-LAAM plus dinor-LAAM)] with microsomes and CYP3A4 decreased with increasing LAAM concentration, suggesting most dinor-LAAM is formed from released nor-LAAM that subsequently reassociates with CYP3A4. Based on these results, we conclude that LAAM and nor-LAAM are predominantly metabolized by CYP3A4 in human liver microsomes, and CYP3A4 exhibits unusual multisite kinetics.

[Politicalchalk]

This part was added later, as a quick pre-text. There is growing research into wether carisoprodol itself is active, some studies suggest that, while it is a prodrug of meprobamate, it is likely active in it's own right. It's also of note that meprobamate actually accumulates in the body from exclusively carisoprodol use under the right conditions in man. Just thought you'd like to know!
----------------------------

Carisoprodol elimination in humans
by
Olsen H, Koppang E, Alvan G, Morland J.
Department of Clinical Pharmacology,
University Hospital, Tromso, Norway.
Ther Drug Monit. 1994 Aug;16(4):337-40.

ABSTRACT

The elimination of the muscle relaxant drug, carisoprodol, was examined in 10 healthy volunteers after an oral dose of 700 mg. In nine subjects, carisoprodol was rapidly eliminated, with a mean half-life of 99 +/- 46 min, and extensively converted to meprobamate. Within 2.5 h after carisoprodol intake, meprobamate serum concentrations exceeded those of carisoprodol. Serum levels of meprobamate recorded (15-25 mumol/L) indicate that meprobamate might contribute to the effect(s) of carisoprodol. One subject eliminated carisoprodol with an overall half-life of 376 min, and only small amounts of meprobamate were recorded. This subject was found to be a poor metabolizer of mephenytoin. In spiked human sera, protein binding of carisoprodol was in the range of 41-67%, whereas meprobamate was bound to a lesser extent, 14-24%.

[Laudaphun]

This is something that SWIM has been meaning to post but just hasn't gotten around to it... But here goes. Anyways of all of the P450s, CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 appear to be the most important forms of, accounting for approximately 15%, 4%, 20%, 5%, 10% and 30%, respectively, of the total human liver P450 content. CYP3A4 alone is responsible for the metabolism of over 50% of teh clincically prescribed drugs metabolized by the liver. CYP3A5 metabolizes similar drugs and ihibitors as CYP3A4, but except for a few drugs is generally less active than CYP3A4.

CYP1A2
Drugs: Acetaminophen, antipyrine, caffeine, clomipramine, phenacetin, tactrine, tamoxifen, theophylline, warfarin
Inducers: Smoking, charcoal-broiled foods, cruciferous vegatables, omeprazole
Inhibitors: Galangin, furafylline, fluvoxamine
CYP2A6
Drugs: Coumarin, tobacco nitrosamines, nicotine (to cotinine and 2'-hydroxynicotine)
Inducers: Rifampin, phenobarbital
Inhibitors: Tranylcypromine, menthofuran, methoxsalen
CYP2B6
Drugs: Artemisinin, bupropion, S-mephobarbital, cyclophosphamide, S-mephenytoin (N-demethylation to nirvanol), propofol, selegiline, sertaline
Inducers: Pheobarbital, cyclophosphamide
Inhibitors: Ticlopidine, clopidogrel
CYP2C8
Drugs: Taxol, all-trans-retinoic acid
Inducers: Rifampin, barbiturates
Inhibitors: Trimethoprim
CYP2C9
Drugs: Celecoxib, flurbiprofen, hexobarbital, ibuprofen, lostan, phenytoin, tolbutamide, trimethadione, sulfaphenazole, S-warfarin, tricrynafen
Inducers: Barbiturates, rifampin
Inhibitors: Tienilic acid, sulfaphenazole
CYP2C18
Drugs Tolbutamide
Inducers: Phenobarbital
Inhibitors:
CYP2C19
Drugs: Diazepam, S-mephenytoin, naproxen, nirvanol, omeprazole, propranolol
Inducers:Barbiturates, rifampin
Inhibitors: N3-benzylnirvanol, N3-benzylphenobarbital, fluconazole
CYP2D6
Drugs: Bufuralol, bupranolol, clomipramine, clozapine, codeine, debrisoquin, dextromethorphan, encainide, flecainide, fluoxetine, guanoxan, haloperidol, hydrocodone, 4-methoxy-amphetamine, metoprolol, mexiletine, oxycodone, paroxetine, phenformin, propafenone, propoxyphene, risperidone, selegiline (deprenyl), sparteine, thioridazine, timolol, tricyclic antidepressants
Inducers: St. John's Wart, rifampin
Inhibitors: Quinidine, paroxetine
CYP2E1
Drugs: Acetaminophen, chlorzoxazone, enflurane, halothane, ethanol (a minor pathway)
Inducers: Ethanol, isoniazid
Inhibitors: 4-Methylpyrazole, disulfiram
CYP34A
Drugs: Acetaminophen, alfentanil, amiodarone, astemizole, cisapride, cocaine, cortisol, cyclosporine, dapsone, diazepam, dihydroergotamine, dihydropyridines, diltiazem, erythromycin, ethinyl estradiol, gestodene, indinavir, lidocaine, lovastatin, macroslides, methadone, micronazole, midazolam, mifepristone (RU 486), nifedipine, paclitaxel, progesterone, quinidine, rapamycin, ritonavir, saquinavir, spironolactone, sulfamethoxazole, sufentanil, tacrolimus, tamoxifen, terfenadine, testosterone, tetrahydrocannabinol, triazolam, troleandomycin, verapamil
Inducers: barbiturates, carbamzepine, glucocorticoids, macrolide antibiotics, pioglitazone, phenytoin, rimapin
Inhibitors: Azamulin, dilitiazam, erythromycin, fluconazole, grapefruit juice (furanocoumarins), itaconazole, ketoconazole, trionavir, troleandomycin.

This list is by no means complete and was taken from a general pharmacology text, "A Primer of Drug Action" by Lange... a book recommended by someone on this website. It was typed up rather quickly and probably contains some typographical errors that will be corrected when SWIM has a few more minutes... When asked in another thread what drugs would be helpful in situations where certain duplicate enzymes were present, however SWIM did not want to suggest medical advise so did not do so. However SWIM had been meaning to type up this list for other SWIMs out there to do as they will with it, hopefully in a responsible fashion. This is a list that SWIM plans to continue to add to and refine as further reading is done.

Laudaphun added 14 Minutes and 45 Seconds later...

Originally Posted by psyche

This is most excellent info. Someone give rep for this because I should spread rep around before giving it again to paracelcus. Didn't know there was a group of people that have faster version of CYP2D6.

Yes, CYP2D6 activity can vary a great deal due to it's highly polymorphic property and the ability of the gene responsible for it's activity to duplicate itself... actually some reading SWIM has read more recently suggests that it might be able to do yet more strange things. SWIM is just beginning to learn about this stuff. Not only are there people who have a faster version of CYP2D6, due to either mutation or gene duplication, but there are people who are at the complete opposite end of the spectrum in that they can actually have very little CYP2D6 activity. Both the enzyme and the gene itself are very interesting...

EDIT: SWIM is holding off until further reading is done to add this to the rest of the list.

Enzyme: CYP3A4
Drug: Buprenorphine - Buprenorphine itself is a kappa antagonist, and a partial agonist at ORL1. Buprenophine is metabolized into norbuprenorphine via N-dealkylation and other metabolites and further cojugated with glucuronic acid and eliminated mainly through excretion into the bile. The metabolite norbuprenorphine is agonist at delta and ORL 1, and the elimination half-life is 20-73 hours (mean 37). Due to the mainly hepatic elimination there is no risk of accumulation in patients with renal impairment and in the elderly. Norburprenorphine, which is the main active metabolite, is a delta and ORL1 receptor agonist, and a mu and kappa receptor partial agonist, however buprenophine antagonizes it's effects. It is thought that the similarties and differences of buprenorphine and norbuprenorphine are responsible for the unique pharmacological profile of buprenorphine.

Just curious but does anyone see something potentially very interesting there?

While CYP3A4 is responsible for metabolizing 75% of buprenorphine, other enzymes yet to be discovered (at least at the time of the publication in Jan 2002 SWIM is reading) are responsible for the metabolism of the other 25%.

J Pharma Experimental Therapeutics. 2001 May;297(2):688-95 and 2002 Jan;300(1):26-33