Drug metabolism and disposition: the biological fate of chemicals
May 1, 2013
Xi-Ling Jiang, Hong-Wu Shen, Donald E Mager et al.
29 citations
Coadministration of the MAO-A inhibitor harmaline sharply increases systemic and brain exposure to the designer drug 5-MeO-DMT and its active metabolite bufotenine in mice. The effect is stronger in wild-type mice than in CYP2D6-humanized mice, because CYP2D6 breaks down 5-MeO-DMT into bufotenine. Surprisingly, a higher harmaline dose (15 mg/kg) reduces bufotenine levels, an effect confirmed in vitro as harmaline also inhibits CYP2D6. A unified pharmacokinetic model describing these interactions was developed and may help predict drug interactions at various doses and in different CYP2D6 genotypes.
Drug metabolism and disposition: the biological fate of chemicals
July 1, 2011
Hong-Wu Shen, Xi-Ling Jiang, Ai-Ming Yu
29 citations
The psychedelic drug 5-MeO-DMT shows nonlinear pharmacokinetics in mice: as the dose increases, the drug's concentration in the body rises more than proportionally. After intravenous or intraperitoneal injections of 2, 10, and 20 mg/kg, dose-normalized blood levels were 1.5- to 2.7-fold higher at the two higher doses compared with the lowest dose. The drug also entered the brain, with brain concentrations increasing nonproportionally with dose. A two-compartment model with nonlinear (Michaelis-Menten) elimination and CYP2D6-dependent linear elimination described the data. These results suggest that the risk of intoxication may increase nonproportionally at higher doses.
Drug metabolism and disposition: the biological fate of chemicals
June 1, 2002
Wenjiang Zhang, Yamini Ramamoorthy, Rachel F Tyndale et al.
17 citations
The ibogaine analog 18-methoxycoronaridine (18-MC) is metabolized primarily into 18-hydroxycoronaridine (18-HC) in human liver microsomes. This conversion is mainly catalyzed by the polymorphic enzyme CYP2C19, with a Michaelis constant (K_m) of 1.34 μM and maximum velocity (V_max) of 0.21 nmol/mg/min. Selective inhibition of CYP2C19 reduced 18-HC formation by 65%, and antibodies against CYP2C enzymes inhibited it by 70%. Other cytochrome P450 enzymes showed negligible involvement. The correlation between 18-MC metabolism and S-mephenytoin 4'-hydroxylase activity across five human liver samples further supports CYP2C19's primary role. These results suggest 18-MC could serve as a probe for CYP2C19 activity.
Drug metabolism and disposition: the biological fate of chemicals
April 28, 2025
Jan Thomann, Deborah Rudin, Selina Kraus et al.
4 citations
A liquid chromatography-tandem mass spectrometry method was developed and validated to measure the recreational psychedelic 2C-B and two of its metabolites (BDMPAA and B-2-HMPAA) in human plasma. The method achieved linear ranges of 0.5–100 ng/mL for 2C-B, 2.5–1000 ng/mL for BDMPAA, and 0.5–1000 ng/mL for B-2-HMPAA with high accuracy and precision. Pharmacokinetic analysis used samples from clinical participants who received 30 mg of 2C-B. Key metabolic enzymes included MAO-A, MAO-B, cytosolic enzymes, and CYP2D6. Unlike 2C-B, the metabolites did not activate the serotonin 2A receptor, indicating they do not contribute to the psychedelic effect. The method provides a reliable tool for future clinical studies.
Drug metabolism and disposition: the biological fate of chemicals
July 1, 2025
Severin Mairinger, Mihye Kwon, Martin Bauer et al.
Systemic absorption of a topically applied drug may not be dose-linear, limiting the usefulness of microdosing to predict therapeutic-dose exposure. In a crossover study of eight healthy participants, a topical microdose of diclofenac (62 μg) resulted in a higher fraction absorbed (0.48%) compared with a therapeutic dose (120 mg, 0.13%), a 3.79-fold difference. Intravenous dosing showed dose-linear disposition. Concentrations in subcutaneous tissue microdialysates were low and variable regardless of dose. The findings indicate that microdosing may not accurately predict the systemic availability of certain topical drugs at therapeutic doses.
Drug metabolism and disposition: the biological fate of chemicals
February 1, 2006
Tooru Kamata, Munehiro Katagi, Hiroe T Kamata et al.
The body breaks down the psychedelic drug 5-MeO-DIPT (also known as 'Foxy') through three main pathways: removal of a methyl group to form 5-OH-DIPT, which is then often conjugated; direct addition of a hydroxyl group to the ring, sometimes followed by methylation, producing 6-OH-5-MeO-DIPT; and removal of an isopropyl group to form 5-MeO-NIPT. The first two metabolites are more abundant than the third. The parent drug can still be detected in urine up to 35 hours after use, but no N-oxide form was found.