Alfentanil Pharmacokinetics and Metabolism in Humans

Meuldermans, W.; Peer, Achlel Van; Hendrickx, Jan; Woestenborghs, Robert; Lauwers, W; Heykants, J; Bussche, G. Vanden; Craeyvelt, Herbert Van; Aa, Paul van der

doi:10.1097/00000542-198810000-00012

Cited by 62 publications

(25 citation statements)

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“…K m values for AMX formation by CYP3A4 and 3A5 were similar, although V max and V max /K m values for CYP3A5 were lower. The in vitro intrinsic clearances were 8-to 25-fold greater for noralfentanil than for AMX formation, suggesting a greater role for piperidine N-dealkylation in alfentanil metabolic inactivation, and consistent with clinical data (Meuldermans et al, 1988).…”

supporting

confidence: 76%

“…Subsequent clinical investigations confirmed that alfentanil metabolism and clearance in vivo are also determined primarily by CYP3A activity (Kharasch et al, 1997(Kharasch et al, , 2004b. Urine noralfentanil accounts for approximately 30% of the dose and 40% of metabolites recovered over 24 h. AMX formation in vivo has not been reported, due possibly to further metabolism to N-(4-hydroxyphenyl)propionamide and N-(4-hydroxyphenyl) acetamide, but amide N-dealkylation accounts for 20 to 25% of the dose and 30% of the 24-h urinary metabolites, indicating the significance of this pathway in vivo as well as in vitro (Meuldermans et al, 1988).…”

mentioning

confidence: 96%

“…Alfentanil is a low-to intermediateextraction drug with low clearance (Ͻ5 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 ), which exhibits considerable interindividiual variability and is proportional to alfentanil hepatic metabolism (Kharasch et al, 2004b). Interindividual variability in alfentanil clearance is therefore attributed to variability in alfentanil metabolism (Meuldermans et al, 1988). Nevertheless, interindividiual variability in alfentanil clearance is otherwise incompletely understood.…”

mentioning

confidence: 99%

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Metabolism of Alfentanil by Cytochrome P4503a (Cyp3a) Enzymes

Klees

Sheffels²,

Dale³

et al. 2004

Drug Metab Dispos

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ABSTRACT:The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b 5 . Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b 5 were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b 5 qualitatively and quantitatively altered alfentanil metabolism, with b 5 coexpression having a greater effect than exogenous addition. Addition or coexpression of b 5 markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to interindividual variability in alfentanil metabolism.

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supporting

confidence: 76%

mentioning

confidence: 96%

mentioning

confidence: 99%

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Metabolism of Alfentanil by Cytochrome P4503a (Cyp3a) Enzymes

Klees

Sheffels²,

Dale³

et al. 2004

Drug Metab Dispos

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“…Both fentanyl and sufentanil are drugs with a high extraction ratio while alfentanil has an intermediate extraction ratio [3,4]. These compounds are metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A to pharmacologically inactive metabolites and show doselinear pharmacokinetics [5][6][7][8][9][10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Correction to: Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review

et al. 2017

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Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R 2 = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R 2 = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R 2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R 2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined.The online version of the original article can be found under

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“…In recent decades, quinazoline-2,4(1H, 3H)-diones have drawn the attention of chemists and medicinal chemists because of their various biological activities for use as anticonvulsants [14], antibacterial [15], psychosedative [16] and antihypertensive or hypotensive compounds [17]. As such, quinazoline-2,4(1H, 3H)-dione derivatives have been widely used as key structures in the production of medicinal drugs [18,19].…”

Section: Introductionmentioning

confidence: 99%