Drug metabolism and disposition : the biological fate of chemicals
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Drug Metab. Dispos. · Jun 2012
ReviewImmune-mediated agranulocytosis caused by the cocaine adulterant levamisole: a case for reactive metabolite(s) involvement.
The United States Public Health Service Administration is alerting medical professionals that a substantial percentage of cocaine imported into the United States is adulterated with levamisole, a veterinary pharmaceutical that can cause blood cell disorders such as severe neutropenia and agranulocytosis. Levamisole was previously approved in combination with fluorouracil for the treatment of colon cancer; however, the drug was withdrawn from the U. S. market in 2000 because of the frequent occurrence of agranulocytosis. ⋯ In this perspective, we provide an historical account of the levamisole/cocaine story as it first surfaced in 2008, including a succinct review of levamisole pharmacology, pharmacokinetics, and preclinical/clinical evidence for levamisole-induced agranulocytosis. Based on the available information on levamisole metabolism in humans, we propose that reactive metabolite formation is the rate-limiting step in the etiology of agranulocytosis associated with levamisole, in a manner similar to other drugs (e.g., propylthiouracil, methimazole, captopril, etc.) associated with blood dyscrasias. Finally, considering the toxicity associated with levamisole, we propose that the 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole scaffold found in levamisole be categorized as a new structural alert, which is to be avoided in drug design.
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Drug Metab. Dispos. · Feb 2012
Mass balance study of [¹⁴C]eribulin in patients with advanced solid tumors.
This mass balance study investigated the metabolism and excretion of eribulin, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single approximately 2 mg (approximately 80 μCi) dose of [¹⁴C]eribulin acetate was administered as a 2 to 5 min bolus injection to six patients on day 1. Blood, urine, and fecal samples were collected at specified time points on days 1 to 8 or until sample radioactivity was ≤1% of the administered dose. ⋯ Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is eliminated primarily unchanged in feces, whereas urine constitutes a minor route of elimination.
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Drug Metab. Dispos. · Dec 2011
Cardiac arrest and therapeutic hypothermia decrease isoform-specific cytochrome P450 drug metabolism.
Mild therapeutic hypothermia is emerging clinically as a neuroprotection therapy for individuals experiencing cardiac arrest (CA); however, its effects combined with disease pathogenesis on drug disposition and response have not been fully elucidated. We determined the activities of four major hepatic-metabolizing enzymes (CYP3A, CYP2C, CYP2D, and CYP2E) during hypothermia after experimental CA in rats by evaluating the pharmacokinetics of their probe drugs as a function of altered body temperature. Animals were randomized into sham normothermia (37.5-38°C), CA normothermia, sham hypothermia (32.5-33°C), and CA hypothermia groups. ⋯ The decreased clearance of chlorzoxazone (CYP2E1) was also associated with CA injury (p < 0.01). Hypothermia was found to be associated with the decreased volume of distribution of midazolam (V(1)), dextromethorphan (V(1)), and peripheral compartment for chlorzoxazone (V(2)) (p < 0.05, p < 0.05, and p < 0.01, respectively). Our data indicate that hypothermia, CA, and their interaction alter cytochrome P450-isoform specific activities in an isoform-specific manner.
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Drug Metab. Dispos. · Oct 2011
Distribution of KAI-9803, a novel δ-protein kinase C inhibitor, after intravenous administration to rats.
KAI-9803 is composed of a selective δ-protein kinase C (δPKC) inhibitor peptide derived from the δV1-1 portion of δPKC (termed "cargo peptide"), conjugated reversibly to the cell-penetrating peptide 11-amino acid, arginine-rich sequence of the HIV type 1 transactivator protein (TAT₄₇₋₅₇; termed "carrier peptide") via a disulfide bond. KAI-9803 administration at the end of ischemia has been found to reduce cardiac damage caused by ischemia-reperfusion in a rat model of acute myocardial infarction. In the study presented here, we examined the TAT₄₇₋₅₇-mediated distribution of KAI-9803 in rats after a single intravenous bolus administration (1 mg/kg). ¹⁴C-KAI-9803 was rapidly delivered to many tissues, including the heart (1.21 μg eq/g tissue), while being quickly cleared from the systemic circulation. ⋯ The tissue distribution of ¹²⁵I-labeled KAI-9803 was compared to that of ¹²⁵I-labeled cargo peptide; this comparison demonstrated that the distribution of KAI-9803 to tissues such as the liver, kidney, and heart was facilitated by the reversible conjugation to TAT₄₇₋₅₇. In an in vitro cardiomyocyte study, the extent of ¹²⁵I-KAI-9803 internalization was greater at 37°C than that at 4°C, whereas the internalization of the ¹²⁵I-cargo peptide at 37°C was not observed, indicating that the uptake of ¹²⁵I-KAI-9803 into the cardiomyocytes was mediated by the TAT₄₇₋₅₇ carrier. Our studies demonstrated that after a single intravenous administration, KAI-9803 can be delivered into the target cells in the liver, kidney, and heart by a TAT₄₇₋₅₇-mediated mechanism.
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Drug Metab. Dispos. · Sep 2011
Randomized Controlled TrialUGT1A6 and UGT2B15 polymorphisms and acetaminophen conjugation in response to a randomized, controlled diet of select fruits and vegetables.
Acetaminophen (APAP) glucuronidation is thought to occur mainly by UDP-glucuronosyltransferases (UGT) in the UGT1A family. Interindividual variation in APAP glucuronidation is attributed in part to polymorphisms in UGT1As. However, evidence suggests that UGT2B15 may also be important. ⋯ APAP half-life was longer in UGT2B15*2/*2 genotypes with F&V (P = 0.009). APAP glucuronidation was significantly influenced by the UGT2B15*2 polymorphism, supporting a role in vivo for UGT2B15 in APAP glucuronidation, whereas the contribution of UGT1A6*2 was modest. Selected F&V known to affect UGT activity led to greater glucuronidation and less sulfation.