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Interaction of Alcohol with Medications and Other Drugs
Published in John Brick, Handbook of the Medical Consequences of Alcohol and Drug Abuse, 2012
John Brick, Mark C. Wallen, William J. Lorman
Many drugs share enzyme systems (e.g., cytochrome P450, alcohol dehydrogenase, aldehyde dehydrogenase) in their biotransformation. When two drugs share the same metabolic pathway, the presence of one drug can alter the metabolism (and thus the bioavailability) of the other drug. For example, beverage alcohol alters the metabolism of methanol by competing for the enzyme that transforms methanol to toxic metabolites. As the metabolism of a drug is an important factor in its bioavailability, changes in drug half-life (the time it takes for the concentration of a drug in circulation to decrease 50 percent) can have significant consequences on the efficacy and toxicity of one or more drugs. Table 16.1 illustrates the amount of drug present with each remaining half-life. If the half-life is increased or decreased by a pharmacokinetic interaction, the amount of drug remaining in the circulation to produce some physiological or psychological change will be proportionally increased or decreased.
Where Are We Today with Imatinib Therapy?
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
The initial phase I study of IM recruited patients with CML who were refractory or resistant to interferon-α (IFN) or intolerant of this agent. The study patients began at an oral dose of 25 mg daily that was escalated in increments to a maximum of 1000 mg daily. The drug half-life was 13 to 16 hours. The drug appeared to be well tolerated and a maximally tolerated dose was not defined. Of the 54 patients who had failed interferon-α and received IM at doses of 300 mg daily or higher, 53 (98%) achieved complete hematologic responses and the majority of responses lasted more than one year (8). In 38 patients with myeloid blast crisis, 21 (55%) responded at imatinib doses of 300 mg/day or greater, but the duration of response for these patients was usually limited (9).
Metronidazole in the Elderly
Published in Thomas T. Yoshikawa, Shobita Rajagopalan, Antibiotic Therapy for Geriatric Patients, 2005
Metronidazole has two principal routes of metabolism including oxidation by hepatic enzymes and urinary excretion of the parent drug and metabolites. It is metabolized in the liver via oxidation to its primary metabolites, the biologically active hydroxy-metabolite (l-2-hydroxyethyl-2-hydroxymethyl-5-nitroimidazole) and the biologically inactive acid metabolite (1-acetic acid-2-methyl-5-nitroimidazole). Both are subsequently excreted in the urine along with any unaltered drug that may have circumvented hepatic metabolism (»5-10% of drug is excreted via the bilary tract). Most studies show a drug half-life (i!/2) of «8-12 hr; this prolonged half-life is further increased in patients with underlying liver disease and impaired oxidation. Although phase I oxidative drug metabolism may be impaired in the elderly, comparative studies of metronidazole elimination in older and younger populations show no age-related differences except for minor alterations in the accumulation of the hydroxy-metabolite (8).
Intravitreal Ranibizumab Versus Aflibercept for Diabetic Macular Edema in Vitrectomized Eyes: 12 Month Results
Published in Seminars in Ophthalmology, 2021
Esra Türkseven Kumral, Nimet Yeşim Erçalık
Diabetic retinopathy is a challenging progressive disease presenting with vitreous hemorrhage, severe microvascular proliferation with tractional retinal detachment affecting or threatening the macula, premacular hemorrhage, and tractional rhegmatogenous retinal detachment. Vitrectomy is commonly applied when these complications occur.7 However, it was suggested that the pharmacokinetics of intravitreally injected drugs were different in vitrectomized eyes.8,9 Drugs are believed to be more rapidly distributed in the vitrectomized eye than an eye with an intact vitreous gel. This results in the shortening of the drug half-life. Although many studies evaluated the effect of anti-VEGF drugs, these two drugs were not compared clinically in vitrectomized human eyes. We aimed to investigate the clinical effects of ranibizumab and aflibercept and compare their effects on CMT, visual acuity, and the number of intravitreal injections in previously vitrectomized eyes.
A review of a diazepam nasal spray for the treatment of acute seizure clusters and prolonged seizures
Published in Expert Review of Neurotherapeutics, 2021
Lindsay M. Higdon, Michael R. Sperling
An open-label study compared the bioavailability of the newer formulation of IN diazepam to oral and rectal diazepam in healthy controls [17]. The time to maximum plasma concentration (tmax) for the IN diazepam was comparable to PR diazepam under ‘ideal conditions’ for rectal absorption (fasting state, enema night prior and 1 hour prior to diazepam PR dose). (Figure 2) Variability in Cmax and AUC0-∞ was lowest with oral diazepam, followed by diazepam nasal spray, and then rectal diazepam. Variability likely relates to both absorption characteristics and drug leakage, which appears greater with rectal administration than nasal dosing. Analysis revealed bioavailability of intranasal diazepam was similar to or greater than rectal diazepam at the 20 mg IN dose (used in 76–111 kg subjects) and that bioavailability was slightly lower for the 15 mg IN dose (used in 51–75 kg subjects) compared to rectal dosing, thought to be due to variability of rectal absorption. Nasal dosing has slightly less bioavailability than oral dosing [17]. (Figure 3) Plasma concentration of the IN formulation peaks approximately 1.5 hours after administration and absolute bioavailability is 97%. Metabolism is mainly hepatic (CYP2C19 and CYP3A4) as well as glucuronidation. Drug half-life is 49 hours, though effective antiseizure half-life is shorter because of distribution to adipose tissue [18].
Voxelotor for the treatment of sickle cell disease
Published in Expert Review of Hematology, 2021
Madhav Vissa, Elliott Vichinsky
Voxelotor is an oral agent that reaches peak plasma concentration in approximately 2 hours. It has a high partitioning into red blood cells and reaches its peak erythrocyte concentration in 6–18 hours after administration with an erythrocyte:plasma ratio of 150:1. Pharmacokinetic studies show a linear, dose-dependent increase in drug concentration in plasma, whole blood and red blood cells. Steady-state concentration is achieved after 8 days of repeated dosing. Drug half-life is 35.5 hours in humans though it ranged from 12 to 66 hours when studied in other animal models [4]. Pharmacokinetics are similar between adults and adolescents ≥12 years of age. Voxelotor is well absorbed with or without food; however, bioavailability after a high-fat, high-calorie meal is higher than during a fasting state. These pharmacokinetic data suggest that once daily dosing would be sufficient to maintain the erythrocyte response [22].