Metabolism of methamphetamine, amphetamine and p-hydroxymethamphetamine by rat-liver microsomal preparations<i>in vitro</i>

Yamamoto, Tetsuro; Takano, Ritsuko; Egashira, T.; Yamanaka, Yasumitsu

doi:10.3109/00498258409151485

Cited by 20 publications

(4 citation statements)

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“…In in vitro metabolic studies of methamphetamine using rat liver fractions, both reduction and oxidation were confirmed. N-hydroxymethamphetamine was reduced to methamphetamine by the non-P450 enzyme in rat liver microsome (Yamamoto et al, 1984), and methamphetamine was oxidized to N-hydroxymethamphetamine in a 10 000 × g supernatant of rat liver (Coutts and Kovach, 1977). Our results are supported by these in vitro studies.…”

Section: Urinary Excretion Profiles After Oral Mdma Administration: Csupporting

confidence: 85%

Urinary excretion profiles ofN-hydroxy-3,4-methylenedioxymethamphetamine in rats

et al. 2011

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N-hydroxy-3,4-methylenedioxymethamphetamine (N-OH-MDMA) is a psychedelic illicit drug that has recently been circulating in Japan. The aims of this study were (i) to optimise enzymatic hydrolysis conditions of the conjugated forms of N-OH-MDMA and its demethylated metabolite N-hydroxy-3,4-methylenedioxyamphetamine (N-OH-MDA), (ii) to investigate the urinary excretion profiles of N-OH-MDMA in rats, and (iii) to compare urinary excretion profiles of N-OH-MDMA and 3,4-methylenedioxymethamphetamine (MDMA). Conjugated forms of the N-hydroxylated compounds (N-OH-MDMA and N-OH-MDA) were almost successfully hydrolysed to their nonconjugated forms under anaerobic conditions after helium purging of the solution. The sum of N-OH-MDMA and N-OH-MDA was used to evaluate the amount of excreted N-hydroxylated metabolites because of degradation of N-OH-MDMA to N-OH-MDA during hydrolysis. Up to 24 h after oral administration of N-OH-MDMA oxalate, the main urinary metabolites were MDMA (14.3% of dose) and 3,4-MDA (7.7% of dose). Most of the N-hydroxylated forms were excreted as glucuronide conjugates. The total amount of N-hydroxylated metabolites after hydrolysis was 1.1% of dose. Urinary excretion profiles of MDMA were similar to that of N-OH-MDMA. It may be difficult to differentiate between abuse of MDMA and N-OH-MDMA by urine analysis.

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Section: Urinary Excretion Profiles After Oral Mdma Administration: Csupporting

confidence: 85%

Urinary excretion profiles ofN-hydroxy-3,4-methylenedioxymethamphetamine in rats

et al. 2011

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“…Phenobarbital-induced CYP2B1 and CYP2B2 are the major CYP2B enzymes from rat and metabolize a wide range of compounds including coumarins [87], steroids [88], and amphetamines [89]. The β-naphthoflavone induced CYP1A1 is associated with metabolism of polycyclic hydrocarbons such as benzo(a)pyrene [90] but metabolizes many of the same compounds as CYP2B1 and CYP2B2.…”

Section: Nmr Of Drugs and Cytochromes P450mentioning

confidence: 99%

Structural Features of Cytochromes P450 and Ligands that Affect Drug Metabolism as Revealed by X-Ray Crystallography and NMR

Roberts

Halpert

2010

Future Med. Chem.

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SUMMARYCytochromes P450 (P450s) play a major role in the clearance of drugs, toxins, and environmental pollutants. Additionally, metabolism by P450s can result in toxic or carcinogenic products. The metabolism of pharmaceuticals by P450s is a major concern during the design of new drug candidates. Determining the interactions between P450s and compounds of very diverse structures is complicated by the variability in P450-ligand interactions. Understanding the protein structural elements and the chemical attributes of ligands that dictate their orientation in the P450 active site will aid in the development of effective and safe therapeutic agents. The goal of this review is to describe P450-ligand interactions from two perspectives. The first is the various structural elements that microsomal P450s have at their disposal to assume the different conformations observed in X-ray crystal structures. The second is P450-ligand dynamics analyzed by NMR relaxation studies.

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“…For example, MDMA pretreated rats that were tolerant to the effects of MDMA exhibited a sensitised response to amphetamine challenge (Callaway and Geyer, 1992a). Amphetamine and MDMA are metabolised via similar pathways (Yamamoto et al, 1984;Kumagai et al, 1994), therefore the pharmacokinetics explanation could not account for these differences. Since diminished 5-HT levels have potentiated the locomotor response to amphetamine (Segal, 1976), it is most likely that these differential responses were attributable to MDMA-induced 5-HT depletions.…”

Section: Effects Of Mdma Pretreatmentmentioning

confidence: 99%

A Behavioural Analysis of Serotonergic Functional Status Following MDMA Exposure

Brennan¹

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<p>Rationale +/- 3,4-Methylenedioxymethamphetamine (MDMA) produces effects on a number of neurochemical systems. Many studies have shown that repeated MDMA administration produces deficits in central serotonergic neurotransmission, which have been suggested to underlie some of the behavioural changes associated with use. Objectives The present studies sought to evaluate the functional statuses of the serotonin transporter (SERT) and the serotonin2c (5-HT2c) and serotonin2a (5-HT2a) receptors following treatment with MDMA to determine whether behavioural deficits could be attributed to alterations in these proteins. Methods Rats received a pretreatment regimen of MDMA (4 x 10mg/kg MDMA injections administered at 2h intervals) or the saline vehicle and, 2 weeks later, [3H] paroxetine binding was undertaken to assess densities of SERT. In other groups, dose-effect curves for MDMA-produced hyperactivity were determined. Additional groups were tested following a 12-week withdrawal period from MDMA in order to assess whether there was recovery of function. The functional status of the SERT was further examined by determining the effect of MDMA pretreatment on the reduction in MDMA-produced hyperactivity (0.0 - 10.0mg/kg) produced by the selective serotonin reuptake inhibitor, clomipramine (0.0 - 5.0mg/kg). The ability for the 5-HT2c receptor agonist, m-CPP (0.0 - 2.5mg/kg) to produce hypolocomotion or increased emergence latency or for the 5-HT2a receptor agonist, DOI (0.0 - 2.0mg/kg) to produce wetdog shakes (WDS) were examined in MDMA pretreated rats. The ability for the 5-HT2c receptors to modulate MDMA-produced hyperactivity was assessed by examining the effect of MDMA pretreatment on the potentiation of MDMA-produced hyperactivity produced by the selective antagonist, RS102221 (0.0 - 1.0mg/kg). Conversely, the modulatory abilities of the 5-HT2a receptors were assessed by examining the effect of MDMA pretreatment on the attenuation of MDMA-produced hyperactivity produced by the antagonist, ritanserin (0.0 - 10.0mg/kg). Results MDMA pretreatment produced widespread reductions in SERT binding densities 2 weeks following administration. Prior exposure to MDMA rendered rats tolerant to MDMA-produced hyperactivity when tested 2, but not 12, weeks following MDMA administration. Two weeks following MDMA pretreatment rats were also less responsive to the clomipramine-produced attenuation of MDMA-produced hyperactivity. MDMA pretreatment failed to alter M-CPP -produced hypolocomotion or increased emergence latency, but decreased the ability for DOI to induce WDS. Further, MDMA pretreated rats exhibited tolerance to RS102221 as shown by a rightward shift in the dose effect curve and complete tolerance to ritanserin. Conclusions Following MDMA pretreatment, the decreased SERT binding densities and inability of clomipramine to attenuate MDMA-produced effects might explain tolerance to the locomotor activating effects produced by MDMA. Functional recovery also occurred with extended abstinence from the drug, suggesting that MDMA produced transient serotonergic alterations. The results support the idea that the 5-HT2a and 5-HT2c receptors that modulate MDMA-produced hyperactivity are functionally distinct from the receptors that mediate m-CPP- and DOI-induced behavioural responses, as m-CPP-produced behaviours were resilient, yet RS102221-induced effects were reduced, by MDMA pretreatment. RS102221 is highly selective in comparison to ritanserin, yet there was only one dose that produced significant potentiation of MDMA-produced hyperactivity, whereas there were several effective ritanserin doses. This suggests that the 5-HT2a receptors had a greater role in modulating MDMA-produced hyperactivity. Additionally, 5-HT2a receptors might be more susceptible to MDMA-induced desensitisation than 5-HT2c receptors, as MDMA pretreated rats exhibited some tolerance to the potentiating effects of RS102221 but were unresponsive to any ritanserin dose. In conclusion, MDMA-induced locomotor tolerance was attributable to decreased SERT densities and function as well as desensitisation of 5-HT2a receptors that facilitate hyperactivity.</p>

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Metabolism of methamphetamine, amphetamine and p-hydroxymethamphetamine by rat-liver microsomal preparationsin vitro

Cited by 20 publications

References 17 publications

Urinary excretion profiles ofN-hydroxy-3,4-methylenedioxymethamphetamine in rats

Urinary excretion profiles ofN-hydroxy-3,4-methylenedioxymethamphetamine in rats

Structural Features of Cytochromes P450 and Ligands that Affect Drug Metabolism as Revealed by X-Ray Crystallography and NMR

A Behavioural Analysis of Serotonergic Functional Status Following MDMA Exposure

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