Metabolism of Lorazepam

Elliott, Henry W.

doi:10.1093/bja/48.10.1017

Cited by 68 publications

(16 citation statements)

References 2 publications

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“…Our results suggest that the cat does not have functional homologues to the human UGT1A6 and UGT2B7, while glucuronidation capacity in the liver is present that may be catalyzed by UGTs that have functional similarities to the human UGT1A1 and possibly other UGT1A isozymes. Indeed, there are some examples of drugs that are well glucuronidated by cats: phenolphthalein (Pekanmaki & Salmi, ; Watkins & Klaassen, ), lorazepam (Schillings et al ., ; Elliott, ; Ruelius, ), pradofloxacin (EMEA/V/C/099, 2007), ibuprofen (Magdalou et al ., ), and telmisartan (Ebner et al ., ) can be found as glucuronides in cats. Telmisartan and ibuprofen are even glucuronidated with a higher rate in feline hepatic microsomes than in other species.…”

Section: Discussionmentioning

confidence: 99%

Comparing the glucuronidation capacity of the feline liver with substrate‐specific glucuronidation in dogs

Beusekom

Fink‐Gremmels

Schrickx

2013

Vet Pharm & Therapeutics

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This study aimed to assess the overall glucuronidation capacity of cats, using prototypic substrates identified for human UDP-glucuronosyltransferases (UGTs). To this end, Michaelis-Menten kinetics were established for the substrates using feline hepatic microsomal fractions, and results were compared with similar experiments carried out with dog liver microsomes. Cats are known for their low capacity of glucuronide formation, and UGT1A6 was found to be a pseudogene. However, functional studies with typical substrates were not performed and knowledge of the enzymology and genetics of other glucuronidation enzymes in felidae is lacking. The results of this study showed extremely low formation of naphthol-1-glucuronide (1.7 ± 0.4 nmol/mg protein/min), estradiol-17-glucuronide (<0.7 nmol/mg protein/min), and morphine-3-glucuronide (0.2 ± 0.03 nmol/mg protein/min), suggesting a lack of functional UGT1A6 and UGT2B7 homologues in the cat's liver. Dog liver microsomes were producing these glucuronides in much higher amounts. Glucuronide capacity was present for the substrates 17β-estradiol (estradiol-3-glucuronide, 2.9 ± 0.2 nmol/mg protein/min) and 4-methylumbelliferone (31.3 ± 3.3 nmol/mg protein/min), assuming that cats have functional homologue enzymes to at least the human UGT1A1 and probably other UGT1A isozymes. This implies that for new drugs, glucuronidation capacity has to be investigated on a substance-to-substance base. Knowledge of the glucuronidation rate of a drug provides the basis for pharmacokinetic modeling and as a result proper dosage regimens can be established to avoid undesirable drug toxicity in cats.

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Section: Discussionmentioning

confidence: 99%

Comparing the glucuronidation capacity of the feline liver with substrate‐specific glucuronidation in dogs

Beusekom

Fink‐Gremmels

Schrickx

2013

Vet Pharm & Therapeutics

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“…The glucuronide metabolite is inactive. [31] Clinical experience with this agent in the neonate is largely restricted to its use as an anticonvulsant [32.33] but it may also be administered for its sedative properties.f15]…”

Section: Lorazepammentioning

confidence: 99%

Clinical Pharmacokinetics of Sedatives in Neonates

Jacqz-Aigrain

Burtin

1996

Clinical Pharmacokinetics

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Sedation is currently administered to neonates experiencing pain and stress during intensive care for medical diseases, as well as postoperatively. Drugs commonly used for sedation in neonates include benzodiazepines (midazolam and lorazepam), chloral hydrate and opioids (fentanyl and morphine). Sedation protocols and dosage schedules are, in most cases, adapted from those which have been developed in children and even adults. The effectiveness and safety of the sedative agents remain underevaluated, however, due to the difficulties of quantifying pain and stress in neonates, and because of the limited use of validated scoring methods by practitioners. Among the benzodiazepines, midazolam is probably the drug of choice for continuous sedation. However, its elimination is delayed in the neonatal period and hypotension may occur when given as a bolus injection or when taken with opioids. Lorazepam requires further evaluation to exclude severe neurotoxicity. Chloral hydrate is administered orally, but because of its delayed elimination and risk of accumulation, a single administration for short term sedation is recommended. Among opioids, fentanyl (which was initially administered for postoperative analgesia) is now prescribed for sedation during mechanical ventilation. Tolerance and dependence may develop rapidly, limiting its usefulness for prolonged sedation. Although extensively studied in neonates, the efficacy and safety of morphine are not clearly determined, because of the limited number of patients included in individual studies. In addition, important interindividual differences in metabolism render dosage recommendations difficult. Alfentanil and sufentanil need further investigations to define their pharmacokinetic-pharmacodynamic properties in neonates. Although the choice of drug is important, the way the drug is used and monitored is equally important. All the drugs used for the sedation of neonates have large inter- and intraindividual differences in disposition, justifying specific pharmacological knowledge and individual dosage adjustments based on clinical evaluation of the patient and the monitoring of drug concentrations.

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“…The two principal pathways of the benzodiazepine biotransformation involve hepatic microsomal oxidation ( N -dealkylation or aliphatic hydroxylation) and glucuronide conjugation (Fig. by age, disease states and concurrent (Elliott 1976;Klotz and Reimann 1980;Heizmann et al 1983;Inaba et al 1988;Park et al 1989;Wandel et al 1994). Microsomal oxidation reactions are catalysed by cytochrome P450 (CYP) isoenzymes 3A4/3A5 and 2C19.…”

Section: Pharmacokinetics and Biotransformationmentioning

confidence: 99%

Midazolam and Other Benzodiazepines

Olkkola

Ahonen

Handbook of Experimental Pharmacology

405

267

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The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.

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Metabolism of Lorazepam

Cited by 68 publications

References 2 publications

Comparing the glucuronidation capacity of the feline liver with substrate‐specific glucuronidation in dogs

Comparing the glucuronidation capacity of the feline liver with substrate‐specific glucuronidation in dogs

Clinical Pharmacokinetics of Sedatives in Neonates

Midazolam and Other Benzodiazepines

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