Disposition and miotic effects of oral alfentanil: A potential noninvasive probe for first‐pass cytochrome P4503A activity

Kharasch, Evan D.; Hoffer, Christine; Walker, Alysa; Sheffels, Pamela

doi:10.1067/mcp.2003.30

Cited by 29 publications

(61 citation statements)

References 17 publications

(36 reference statements)

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“…In addition, alfentanil causes pupil constriction (miosis) that is essentially log-linear between 10 and 100 ng/ml, and the time course of alfentanil-dependent miosis mirrors that of alfentanil plasma concentrations. Thus, miosis is a surrogate for plasma concentration and, hence, alfentanil miosis is a noninvasive in vivo probe for hepatic and first-pass CYP3A activity (Phimmasone and Kharasch, 2001;Kharasch et al, 2003Kharasch et al, , 2004bKharasch et al, , 2005.…”

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confidence: 99%

“…Alfentanil has been used as an in vivo probe for hepatic and first-pass CYP3A activity and drug interactions, due to the considerable dependence of alfentanil clearance on CYP3A activity (Kharasch et al, 1997(Kharasch et al, , 2003(Kharasch et al, , 2004b(Kharasch et al, , 2005Phimmasone and Kharasch, 2001). In addition, alfentanil causes pupil constriction (miosis) that is essentially log-linear between 10 and 100 ng/ml, and the time course of alfentanil-dependent miosis mirrors that of alfentanil plasma concentrations.…”

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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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confidence: 99%

Metabolism of Alfentanil by Cytochrome P4503a (Cyp3a) Enzymes

Klees

Sheffels²,

Dale³

et al. 2004

Drug Metab Dispos

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“…A 20-to 250-fold variability in CYP2B6 expression has been reported [94,113]. In addition, there is a significant variation in the hepatic expression of CYP3A4 based on in vitro (35-100-fold) studies using human liver bank [114] and in vivo (20-50-fold) using probe drugs such as erythromycin [115], midazolam [116], and alfentanil [117]. Such a substantial variation is considered to be the result of a number of environmental, physiological and genetic factors affecting the activity and expression of CYP3A4 [118].…”

Section: Pharmacokinetics Of Oxazaphosphorinesmentioning

confidence: 99%

Design of New Oxazaphosphorine Anticancer Drugs

Liang¹,

Huang²,

Duan³

et al. 2007

CPD

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The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, beta-D-glucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a beta-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)-bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.

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“…A 20-to 250-fold variability in CYP2B6 expression has been reported [170,171]. In addition, there is a significant variation in the hepatic expression of CYP3A4 based on in vitro (35-100-fold) studies using human liver bank [172] and in vivo (20-50-fold) using probe drugs such as erythromycin [173] and midazolam [174], and alfentanil [175]. Such a substantial variation is considered to be the result of a number of environmental, physiological and genetic factors [176].…”

Section: Pharmacokinetics Of Oxazaphosphorinesmentioning

confidence: 99%

Reversal of Resistance to Oxazaphosphorines

Zhang¹,

Tian²,

Zhu³

et al. 2006

CCDT

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The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO) and trofosfamide are one important group of alkylating agents. However, resistance is the major hindrance for success of oxazaphosphorine chemotherapy. The mechanism of resistance to oxazaphosphorines is not fully identified, but recently some novel insights into these aspects have been generated by using sensitive analytical techniques and powerful pharmacogenetic techniques. Potential mechanisms for oxazaphosphorine resistance include decreased activation by cytochrome P450s (e.g. CYP3A4, CYP2C9 and CYP2B6), increased deactivation of the agents by deactivating enzymes such as aldehyde dehydrogenases (ALDHs), increased cellular thiol level, increased DNA repair capacity, and altered cellular apoptotic response to DNA repair, e.g. deficient apoptosis due to lack of cellular mechanisms to result in cell death following DNA damage. In addition, decreased cellular accumulation of cytotoxic species of oxazaphosphorines may also play a role in the resistance. This review highlights the pharmacology of oxazaphosphorine anticancer drugs and possible agents that reverse the resistance to these agents. Possible agents that can overcome oxazaphosphorine resistance include inducers of CYPs, modulators of GSTs and ALDHs, modulators of DNA repair process, antisense oligonucleotides against genes encoding various enzymes and signalling proteins, and novel gene delivery systems. Most of these agents have been investigated in preclinical studies and promising results have been observed. To date, several types of these agents are being evaluated in Phase III trials in cancer patients. Further studies are needed to identify the molecular targets associated with resistance to oxazaphosphorines.

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Disposition and miotic effects of oral alfentanil: A potential noninvasive probe for first‐pass cytochrome P4503A activity

Cited by 29 publications

References 17 publications

Metabolism of Alfentanil by Cytochrome P4503a (Cyp3a) Enzymes

Metabolism of Alfentanil by Cytochrome P4503a (Cyp3a) Enzymes

Design of New Oxazaphosphorine Anticancer Drugs

Reversal of Resistance to Oxazaphosphorines

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