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Pharmacokinetics of Amphetamines: In Vivo and in Vitro Studies of Factors Governing Their Elimination
Published in John Caldwell, S. Joseph Mulé, Amphetamines and Related Stimulants: Chemical, Biological, Clinical, and Sociological Aspects, 2019
Measuring the difference spectra of microsomes in the presence of a wide range of concentrations of D-(+)-N-methylamphetamine and cytochrome P-450 (a type I binding spectrum)74 reveals a complex Lineweaver Burke plot,75 which can be explained by the presence of distinctly binding sites, each with its own affinity (Ks value). D-(+)-N-dimethylamphetamine on the contrary shows a linear Lineweaver Burke plot, indicating one binding site. These data are confirmed by the results of measurements of metabolic rates at different substrate concentrations. For the N-dimethylamphetamines normal Lineweaver Burke plots were found, while N-methylamphetamines show a complex Lineweaver Burke plot (Figures 9A and 9B). The N-demethylation of the secondary amine, N-methylamphetamine, shows a manifest stereoselectivity, in contrast to the tertiary amine, N-dimethylamphetamine (Figure 9). The complex Lineweaver Burke plots seen for the secondary amines may be the result of (1) a negative cooperativity which means that at higher substrate concentrations the conversion is facilitated, (2) two different binding sites, or (3) binding sites on two different enzymes. Studies of the in vitro metabolism of these compounds in subcellular preparations have revealed that amphetamines are metabolized by different enzyme identities.
Flumazenil partially reverses gamma-hydroxybutyrate (GHB)-induced coma: a case report
Published in The American Journal of Drug and Alcohol Abuse, 2022
Shiao-Yu Chen, Feng-Yuan Chu, Chih-Yu Yang, Der-Cherng Tarng
A 34-year-old man without underlying diseases was sent to the emergency room (ER) by his roommate due to unconsciousness. According to his roommate’s statement, the patient went to bed at 2 a.m. Around 3 a.m., he noticed that the patient had vomited once, but he could still respond to questions at that time. However, the patient was found unconscious and unresponsive when an alarm clock went off later that morning. At ER arrival at 6 a.m., his body temperature was 35.8°C and his consciousness level was E1V1M1 [3 of 15 from Glasgow Coma Scale (GCS)]. Bilateral pupils showed 2 mm in size with prompt reflex. Muscle power was 0 to 1 point. Bilateral Babinski, Kernig, and Brudzinski signs were negative. Endotracheal intubation was performed to provide airway support. Blood biochemistry and urinalysis tests in the ER were normal. Electrocardiography and chest X-ray showed no specific abnormal findings. Brain computed tomographic (CT) scan showed no intracranial hemorrhage, major artery occlusion, filling defect, or ischemic region. Blood levels of ethyl alcohol, aspirin, acetaminophen, phenobarbital, lithium, and tricyclic antidepressants were undetectable. Flumazenil 0.5 mg was administered, and the patient’s GCS level improved immediately to E1VTM4. Patient could also move all four limbs weakly in response to stimuli, but eyes remained closed, and he was not trying to speak. However, the GCS level decreased to E1VTM1 one minute after flumazenil administration. One hour later, a second dose of flumazenil 0.5 mg was given again for diagnostic purposes by a toxicology consultant, and the patient responded similarly. Ten hours after GHB ingestion (i.e., 3 hours post flumazenil), patient was fully awake. After extubation, patient acknowledged misuse of 20cc gamma-hydroxybutyrate (GHB) with an unknown concentration at about 2 a.m. in a suicide attempt because of depressed mood. He declared that he had used GHB 2cc per time for insomnia 1–2 times per month in recent 6 months. He denied any other hypnotic drug use. He was discharged without complications. Urine toxicology, obtained 5 hours after GHB ingestion, showed GHB level was 1,725 mg/L (5–10 mg/L distinguishes between endogenous and exogenous concentrations)(2); methamphetamine 79.3 mg/L (ref range <0.5 mg/L), amphetamine 4.91 mg/L (ref range <0.1 mg/L); N,N-Dimethylamphetamine 1.024 mg/L (positive). Benzodiazepine (BZD), morphine, cocaine, cannabinoids, phencyclidine, and barbiturates tested negative. The patient’s consent was obtained, and the Institutional Review Board of the Taipei Veterans General Hospital approved the case report.