Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: Noninvasive assessment by use of pupillary miosis

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

doi:10.1016/j.clpt.2004.07.006

Cited by 111 publications

(146 citation statements)

References 56 publications

(178 reference statements)

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“…When midazolam was administrated intravenously, the average induction of midazolam clearance by rifampicin was reported to be 2-fold (Floyd et al, 2003;Gorski et al, 2004;Kharasch et al, 2004;Yu et al, 2004). In the study by Gorski et al (2004), the range of induction of midazolam clearance by rifampicin was reported to be between 1.4-and 7.4-fold.…”

Section: Discussionmentioning

confidence: 92%

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Darnell¹,

Schreiter²,

Zeilinger³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Reliable and stable in vitro cellular systems maintaining specific liver functions important for drug metabolism and disposition are urgently needed in preclinical drug discovery and development research. The cell line HepaRG exhibits promising properties such as expression and function of drug-metabolizing enzymes and transporter proteins, which resemble those found in freshly isolated human hepatocytes. In this study, HepaRG cells were cultured up to 68 days in a three-dimensional multicompartment capillary membrane bioreactor, which enables high-density cell culture under dynamic conditions. The activity of drug-metabolizing cytochrome P450 (P450) enzymes was investigated by a cocktail of substrates for CYP1A1/2 (phenacetin), CYP2C9 (diclofenac), CYP2B6 (bupropion), and CYP3A4 (midazolam). The model P450 substrates, which were introduced to the bioreactor system mimicking in vivo bolus doses, showed stable metabolism over the entire experimental period of several weeks with the exception of bupropion hydroxylase, which increased over time. Ketoconazole treatment decreased the CYP3A4 activity by 69%, and rifampicin induced the CYP3A4-and CYP2B6-dependent activity 6-fold, which predicts well the magnitude of changes observed in vivo. Moreover, polarity of transporter expression and formation of tissue-like structures including bile canaliculi were demonstrated by immune histochemistry. The long-lasting bioreactor system using HepaRG cells thus provides a promising and stable liver-like in vitro model for continuous investigations of the hepatic kinetics of drugs and of drug-drug interactions, which well predict the situation in vivo in humans.

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Section: Discussionmentioning

confidence: 92%

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Darnell¹,

Schreiter²,

Zeilinger³

et al. 2011

Drug Metab Dispos

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“…Hepatic CYP3A activity was evaluated on day 2 using i.v. alfentanil as an in vivo probe (Kharasch et al, 2004b(Kharasch et al, , 2008b(Kharasch et al, , 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a. Subjects received ondansetron followed 30 minutes later by alfentanil bolus (15 and 5 mg/kg at control and ritonavir-lopinavir sessions, respectively).…”

Section: Methodsmentioning

confidence: 99%

“…First-pass CYP3A activity and intestinal P-gp (and other transporters) activity were evaluated on day 1 using oral alfentanil and fexofenadine as in vivo probes (Kharasch et al, 2004b(Kharasch et al, , 2005(Kharasch et al, , 2008b(Kharasch et al, , 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a. Subjects received ondansetron (4 mg i.v.)…”

Section: Methodsmentioning

confidence: 99%

“…A comprehensive crossover investigation in healthy volunteers evaluated the metabolism and clearance of both intravenous and oral methadone. Clearances of intravenous and oral alfentanil, a nonselective CYP3A4/5 (henceforth referred to as CYP3A) substrate, phenotyped hepatic and first-pass CYP3A activities and oral fexofenadine probed P-gp (Kharasch et al, 2004b(Kharasch et al, , 2005(Kharasch et al, , 2008a(Kharasch et al, ,b, 2009a(Kharasch et al, ,b, 2011a(Kharasch et al, ,b, 2012a.…”

Section: Introductionmentioning

confidence: 99%

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Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Kharasch

Stubbert

2013

Drug Metab Dispos

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Plasma concentrations of orally administered methadone are reduced by the human immunodeficiency virus protease inhibitor combination ritonavir and lopinavir, but the mechanism is unknown. Methadone metabolism, clearance, and drug interactions have been attributed to CYP3A4, but this remains controversial. This investigation assessed the effects of acute (2 days) and steady-state (2 weeks) ritonavirlopinavir on intravenous and oral methadone metabolism and clearance, hepatic and intestinal CYP3A4/5 activity (using the probe substrate intravenous and oral alfentanil), and intestinal transporter activity (using oral fexofenadine) in healthy volunteers. Plasma and urine concentrations of methadone and metabolite enantiomers, and other analytes, were determined by mass spectrometry. Acute and chronic ritonavir-lopinavir reduced plasma methadone enantiomer concentrations in half, with an average 2.6-and 1.5-fold induction of systemic and apparent oral methadone clearances. Induction was attributable to stereoselectively increased hepatic methadone N-demethylation, hepatic extraction, and hepatic clearance, and there was a strong correlation between methadone N-demethylation and clearance. Methadone renal clearance was unchanged. Alfentanil's systemic clearance and hepatic extraction, apparent oral clearance, and intestinal extraction were reduced to 25%, 16%, and 35% of control, indicating strong inhibition of hepatic and intestinal CYP3A activities. Ritonavir-lopinavir (acute > chronic) increased fexofenadine exposure, suggesting intestinal P-glycoprotein inhibition. No correlation was found between methadone clearance and CYP3A activity. Acute and steady-state ritonavir-lopinavir stereoselectively induced methadone N-demethylation and clearance, despite significant inhibition of hepatic and intestinal CYP3A activity. Ritonavir-lopinavir inhibited intestinal transporters activity but had no effect on methadone bioavailability. These results do not support a significant role for CYP3A or ritonavir-lopinavir-inhibitable intestinal transporters in single-dose methadone disposition.

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“…B, dose of RIF, 600 mg q.d. The observed DDI data were the means of 9 or 10 subjects (Backman et al, 1996(Backman et al, , 1998Kharasch et al, 2004) for RIF dosed for 5 days, 8 subjects (Link et al, 2008) for RIF dosed for 6 days, 14 subjects (Gorski et al, 2003) for RIF dosed for 7 days, 19 subjects (Chung et al, 2006) for RIF dosed for 9 days, 16 subjects (Adams et al, 2005) for RIF dosed for 14 days, and 57 subjects (Floyd et al, 2003) (Fig. 3, A-C).…”

Section: Prediction Of Multiple Dose Pharmacokinetics Of Cyp3a4mentioning

confidence: 99%

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

Xu¹,

Zhou²,

Hayashi³

et al. 2011

Drug Metab Dispos

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Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: Noninvasive assessment by use of pupillary miosis

Cited by 111 publications

References 56 publications

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Cytochrome P450-Dependent Metabolism in HepaRG Cells Cultured in a Dynamic Three-Dimensional Bioreactor

Cytochrome P4503A Does Not Mediate the Interaction between Methadone and Ritonavir-Lopinavir

Simulation of Clinical Drug-Drug Interactions from Hepatocyte CYP3A4 Induction Data and Its Potential Utility in Trial Designs

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