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Disposition kinetics of the enantiomers of methamphetamine and its metabolites in rats.
Methamphetamine (MAP), the N-methyl derivative of amphetamine (AP), has been abused by human populations in several countries. There are stereoisomeric differences in the pharmacodynamics of the enantiomers with the d-enantiomer of both drugs being more potent than the antipode in its central stimulating effects. The stereoisomeric differences in disposition kinetics of MAP and its metabolites were studied in rats. Several sensitive enantiomer-specific HPLC methods were developed to quantitate enantiomers of MAP and its metabolites in serum and urine samples. The optical isomers of these compounds are derivatized by reacting with a chiral fluorescent reagent, (-)-1-(9-fluorenyl)ethyl chloroformate, before separation on a reverse-phase HPLC column. These methods have sensitivities in the low ng/ml range. Both MAP and AP are low protein-bound drugs. There are slight differences in serum protein binding between MAP enantiomers. The binding of d-AP is greater than l-AP. Following administration of racemic MAP to rats, the serum concentration of the d-enantiomer was higher than the l-enantiomer. The metabolites recovered in urine are enantiomers of MAP, AP, p-hydroxymethamphetamine (OHMAP) and p-hydroxyamphetamine (OHAP). A greater amount of the d-enantiomer of MAP and AP could be recovered compared with the l-enantiomer. The hydroxylated metabolites were excreted as unconjugated and conjugated forms with the total l-enantiomer being higher than the antipode. There are stereoisomeric differences for both clearance and volume of distribution of MAP. When racemic AP was administered, AP and unconjugated and conjugated of OHAP could be recovered in urine. Both clearance and volume of distribution of l-AP are significantly higher than d-AP. The clearance of d-OHMAP is greater than that of l-OHMAP. The change in enantiomeric ratio (l-/d-) of metabolites following MAP compared to that following AP suggested the existence of multiple stereoselective pathways involved in the disposition of these compounds. The differences in serum concentrations between AP enantiomers was magnified following racemic MAP, which suggested stereoselective N-demethylation. There are no differences in disposition kinetics of MAP between Sprague-Dawley and Fisher 344 rats. Activated charcoal given orally 10 minute before an iv dose of racemic MAP did not enhance the elimination of the drug in vivo
Voxelotor (GBT440), a first-in-class hemoglobin oxygen-affinity modulator, has promising and reassuring preclinical and clinical data
Relationship between discriminative stimulus effects and plasma methamphetamine and amphetamine levels of intramuscular methamphetamine in male rhesus monkeys
Cation-selective exhaustive injection and sweeping MEKC for direct analysis of methamphetamine and its metabolites in urine
GBT1118, a compound that increases the oxygen affinity of hemoglobin, improves survival in murine hypoxic acute lung injury
GBT440, a Potent Anti-Sickling Hemoglobin Modifier Reduces Hemolysis, Improves Anemia and Nearly Eliminates Sickle Cells in Peripheral Blood of Patients with Sickle Cell Disease
A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease
New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class, oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin for oxygen, thus inhibiting HbS polymerization and the downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD which was followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg/day) in patients with sickle cell anemia (HbSS). The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof-of-concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg/day, or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg/day, or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg/day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased hemoglobin and reduction in hemolysis and percent of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. ClinicalTrials.gov identification: #NCT02285088 and #NCT03041909