Is the Metabolism of Alfentanil Subject to Debrisoquine Polymorphism? A Study Using Human Liver Microsomes

Lavrijsen, Karel; Houdt, J. M. G. van; Dyck, Dirk M. J. Van; Hendrickx, Jan; Woestenborghs, Robert; Lauwers, W; Meuldermans, W.; Heykants, J

doi:10.1097/00000542-198810000-00013

Cited by 22 publications

(11 citation statements)

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“…Loperamide (4-(p-chlorophenyl)-4-hydroxy-N,N,-dimethyl-␣,␣-diphenyl-1-piperidine butyramide hydrochloride, is an opiate agonist widely used as an effective drug for the control and symptomatic relief of acute non-specific diarrhea [1]. More recently, it has also been reported that loperamide could have some interest as an antihyperalgesic agent reducing pain without any central nervous system side effects [2].…”

Section: Introductionmentioning

confidence: 99%

“…The determination of loperamide in biological fluids for pharmacokinetics studies has also been reported. Radioimmunoassays (RIAs) were used for the quantitation of loperamide in serum and urine [1,10,11] but liquid chromatographic methods involving electrochemical [12], UV [13] or MS detection [14] seem to be preferred due to their higher selectivity. Since the introduction of atmospheric pressure ionization interfaces, the combination of liquid chromatography and mass spectrometry allows to dispose very sensitive and selective methods.…”

Section: Introductionmentioning

confidence: 99%

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Validation of a liquid chromatographic-tandem mass spectrometric method for the determination of loperamide in human plasma

Streel¹,

Ceccato²,

Klinkenberg³

et al. 2005

Journal of Chromatography B

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Validation of a liquid chromatographic-tandem mass spectrometric method for the determination of loperamide in human plasma

Streel¹,

Ceccato²,

Klinkenberg³

et al. 2005

Journal of Chromatography B

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“…Some of these include intestinal slices, shed human enterocytes, Ussing chamber, and gut contents (flora). Isolated gut contents under an anaerobic atmosphere have been used to characterize the reduction of loperamide oxide to its active component [31]. Subsequent in vivo studies suggested that the N-oxide could be a controlled release-type prodrug for loperamide to reduce the incidence of side effects.…”

Section: Other In Vitro Systemsmentioning

confidence: 99%

The Role of the Intestine in Drug Metabolism and Pharmacokinetics: An Industry Perspective

Fisher¹,

Labissiere²

2007

CDM

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Over the past decade, our knowledge concerning the importance of intestinal metabolism in the disposition of xenobiotics has significantly improved. Compounds such as midazolam can be extensively extracted in the intestine upon first-pass metabolism after oral dosing. Conversely, the intestine plays a less important, albeit less characterized role in systemic metabolism. This manuscript is meant to review the published examples of pharmaceutical industry research on the intestinal metabolism of xenobiotics, including the various in vitro and in vivo models used. While it is clear that some examples exist of published characterization of the role of intestinal metabolism in drug disposition from the pharmaceutical industry, the majority of industry literature ignores its contribution. The opportunity exists to increase the examination of intestinal metabolism of drugs and drug candidates in industry.

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“…A threefold increase in alfentanil systemic clearance is demonstrated as a result of rifampicin induction and troleandomycin inhibition results in a four-to fivefold decrease in alfentanil clearance [142,144]. Alfentanil clearance is not associated with CYP2D6 polymorphism in vitro and in vivo [150,151].…”

Section: Cyp450mentioning

confidence: 99%

Individualizing Analgesic Prescription Part I: Pharmacogenetics of Opioid Analgesics

Samer

Desmeules

Dayer

2006

Personalized Medicine

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The current use of analgesics is based on the empiric administration of a given drug with clinical monitoring for efficacy and toxicity. However, individual responses to drugs are influenced by a combination of pharmacokinetic and pharmacodynamic processes, and each of these components, in addition to pain perception and processing, seem to be regulated by genetic factors. Whereas polymorphic drug-metabolizing enzymes and drug transporters may affect the pharmacokinetics of drugs, polymorphic drug targets and disease-related pathways may influence the pharmacodynamic action of drugs. After usual dose, drug toxicity, as well as inefficacy, can be observed depending on the polymorphism, the analgesic considered and the presence or absence of active metabolites. Thus, cytochrome P450 (CYP)2D6 polymorphism influences codeine and tramadol analgesic effects, CYP2C9 has an impact on the disposition of some nonsteroidal anti-inflammatory drugs, and opioid receptor polymorphism (118A>G) may reduce morphine potency. Moreover, drug interaction mimics genetic deficiency and contributes to the variability in response to analgesics. This two-part review summarizes the available data on the pharmacokinetic-pharmacodynamic consequences of known polymorphisms of drug-metabolizing enzymes (CYP and uridine diphosphate glucuronosyltransferase), drug transporters (multidrug resistance proteins, multidrug resistance-associated proteins, organic anion-transporting polypeptides, and serotonin transporters), relevant drug targets (such as µ-opioid receptor, serotonin receptor and cyclooxygenases) and other nonopioid biological systems, on currently prescribed central and peripheral analgesics.

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Is the Metabolism of Alfentanil Subject to Debrisoquine Polymorphism? A Study Using Human Liver Microsomes

Cited by 22 publications

References 0 publications

Validation of a liquid chromatographic-tandem mass spectrometric method for the determination of loperamide in human plasma

Validation of a liquid chromatographic-tandem mass spectrometric method for the determination of loperamide in human plasma

The Role of the Intestine in Drug Metabolism and Pharmacokinetics: An Industry Perspective

Individualizing Analgesic Prescription Part I: Pharmacogenetics of Opioid Analgesics

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