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DRUG METABOLISM |
From the Departments of Anesthesiology and Medicinal Chemistry, University of Washington, Seattle.
Address for reprints: Evan D. Kharasch, Department of Anesthesiology, Box 356540, University of Washington, 1959 NE Pacific St. RR-442, Seattle, WA 98195.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Quinidine • P-glycoprotein • intestinal absorption • fentanyl • drug metabolism
The drug efflux pump P-glycoprotein (P-gp) is located on the luminal surface of brain capillary endothelial cells, where it is an integral component of the blood-brain barrier, actively pumps certain drugs out of the brain, and thereby limits brain access and regulates pharmacologic effects.2-4 P-gp is also expressed on the apical surface of intestinal epithelial cells, where it actively transports drugs back into the gut lumen and limits their oral bioavailability.2,5
Some evidence suggests that fentanyl undergoes P-gp-mediated efflux from the central nervous system. In primary cultured bovine brain microvessel endothelial cells, fentanyl was shown to undergo carrier-mediated active transport.6 Furthermore, fentanyl decreased the release of rhodamine 123 from brain endothelial cells. Together, these results were interpreted to indicate that fentanyl is a P-gp substrate.6 This was further supported by the observation that fentanyl uptake was significantly increased in magnesium-free medium, a condition known to reduce P-gp activity.6 Although loperamide but not fentanyl behaved as a P-gp substrate in L-MDR1 cells expressing P-gp, both fentanyl and loperamide inhibited P-gp-mediated digoxin transport in Caco-2 cells.7 In mice, cyclosporine significantly increased fentanyl analgesia in a dose-dependent manner but itself had no analgesic effects.8 The increase in analgesia was pharmacodynamically mediated since plasma fentanyl concentrations were not changed by cyclosporine.8 In P-gp knockout mice, fentanyl analgesia was significantly increased.9 Thus, fentanyl appears to be a substrate for P-gp in vitro, P-gp in animals may contribute to brain fentanyl access and analgesia, and P-gp-mediated drug interactions can alter fentanyl effects.
The antidiarrheal opioid loperamide acts at intestinal opiate receptors to decrease gut motility but is normally without central nervous system effects because it is efficiently excluded from the brain by P-gp.10 Loperamide was the first opioid evidenced to be a P-gp substrate in humans in vivo.11 Loperamide alone had no effect on breathing but markedly depressed respiration after patients were pretreated with the P-gp inhibitor quinidine.11 An effect of quinidine on loperamide pharmacodynamics was surmised because it was reported to have no effect on plasma loperamide concentrations.11
The observations regarding the role of P-gp in fentanyl transport and analgesia in animals raises the possibility that P-gp may influence brain access and pharmacodynamics of fentanyl in humans. P-gp may also explain important clinical differences between various opioids with respect to their onset times for analgesia. P-gp may also be a clinical determinant of oral fentanyl absorption, bioavailability, and clinical effect. Nevertheless, the role of P-gp in human fentanyl bioavailability, brain access, and clinical effects is essentially unknown. Therefore, the purpose of this investigation was to assess the role of intestinal and brain P-gp in determining plasma concentrations and clinical effects of oral fentanyl, as well as the clinical effects of IV fentanyl in humans. The P-gp inhibitor quinidine, used previously to evaluate the role of P-gp in brain loperamide access,11 was used as an in vivo P-gp probe. The hypothesis was that quinidine would enhance IV fentanyl miosis. When the results did not substantiate this hypothesis, a second protocol was performed, evaluating both plasma concentrations and fentanyl effect, to test the hypothesis that quinidine would enhance oral fentanyl miosis.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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For each session, a catheter was placed in an arm vein for blood sampling or drug administration. Subjects (supine) were monitored with an automated blood pressure cuff and pulse oximeter for 2 hours after opioid administration and received supplemental oxygen for an oxygen saturation less than 94%. After baseline measurements (blood sample and pupil diameter), subjects received either 600 mg oral immediate-release quinidine sulfate or an oral placebo (lactose). Subjects and all investigators were blinded to the identity of the pretreatment. A 12-lead electrocardiogram was obtained before and 0.5, 1, 1.5, 2, 3, and 8 hours after quinidine or placebo.
In the first protocol for evaluating IV fentanyl, 1 hour after receiving quinidine or placebo, subjects were given 2.5 µg/kg fentanyl as a 5-minute infusion via syringe pump. Dark-adapted pupil diameters were measured before and each minute during the fentanyl infusion and 1, 3, 5, 7, 10, 15, 30, 45, 60, 75, 90, 105, 120, 150, 180, 240, 300, 360, and 480 minutes after the end of the infusion, using a Pupilscan Model 12A infrared pupilometer (Keeler USA) as described previously.12 The pupil diameter measurement obtained prior to the fentanyl infusion was taken as the baseline value and used to calculate pupil diameter change at each time point.
The second protocol evaluated oral fentanyl. Thirty minutes after quinidine or placebo, subjects received ondansetron (4 mg IV) for antinausea prophylaxis.a Thirty minutes later, they received 2.5 µg/kg oral fentanyl with 50 cc water. Venous blood samples were obtained before and 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, and 480 minutes after fentanyl dosing. Plasma was separated and stored at -20°C for later analysis. Dark-adapted pupil diameter was measured coincident with blood sampling (and also at 2.5 and 3.5 h). For both protocols, subjects were fed a standard breakfast 2 hours after fentanyl administration and had free access to food and water thereafter, and the washout period between placebo and quinidine sessions was approximately 1 week.
Subjective self-assessment of feelings or mood states was quantified by Visual Analog Scales (VAS) in both protocols. Attributes assessed (and scored from 0-100) included level of alertness/sedation (almost asleep to wide awake), energy level (no energy to full of energy), confusion (confused to clear-headed), clumsiness (extremely clumsy to well coordinated), anxiety (calm/relaxed to extremely nervous), and nausea (no nausea to worst nausea). Tests were given at baseline (prior to quinidine or placebo) and following each pupil diameter measurement after the infusion or oral dosing was completed.
Analytical Methods
Plasma concentrations of fentanyl and norfentanyl were determined by gas chromatography/mass spectrometry (GC/MS) and LC/mass spectrometry (LC/MS), respectively. Fentanyl, norfentanyl, and their pentadeuterated analogs (d5-fentanyl and d5-norfentanyl) were purchased from Cerilliant Corp. (Austin, TX). HPLC-grade methanol and acetonitrile were from Fisher Scientific (Pittsburgh, PA). Oasis MCX solid-phase extraction (SPE) cartridges were obtained from Waters Corp. (Milford, MA). All stock drug solutions, buffers, and HPLC mobile phase were prepared using Milli-Q (Millipore, Bedford, MA) water.
Plasma (1 mL) and the internal standard mix (1 mL 0.1N HCl containing 1 ng each d5-fentanyl and d5-norfentanyl) were mixed in glass tubes and then loaded (0.5 mL/min) onto Oasis MCX SPE cartridges that had been preconditioned with 1 mL methanol followed by 1 mL 0.1N HCl. Cartridges were then washed with 2 mL 0.1N HCl followed by 2 mL methanol and then dried under vacuum. Analytes were eluted by gravity with 2 mL 5% ammonium hydroxide in methanol and evaporated to dryness at 45°C under nitrogen (TurboVap LV, Zymark). Samples were reconstituted in 50 µL methanol for GC/MS or in 50 µL acetonitrile (0.05% TFA)/water (0.05% TFA) (20:80) for LC/MS and transferred into glass autosampler vials for analysis.
The GC/MS assay of fentanyl used an Agilent (Palo Alto, CA) 6890-5973 GC-MSD and a DB-5 (30 m x 0.32 mm x 0.3 µm) capillary column (J & W, Folsom, CA). Injections (2 µL) were made in pulsed splitless and constant-flow (1.6 mL/min) modes. The injector and transfer line temperatures were 250°C and 300°C, respectively. The oven temperature was 150°C for 1 minute, increased to 250°C at 50°C/min, increased to 290°C at 20°C/min, and held at 290°C. Detection used the selected ion mode for fentanyl and d5-fentanyl (m/z 245.1 and 250.1, respectively). Calibration curves (average r2 > 0.99) were obtained by analyzing drug-free plasma fortified with 0.02 to 10 ng/mL fentanyl. Each subject's samples (placebo and quinidine pretreatments) were analyzed on the same day. Interday coefficients of variation were 15%, 10%, and 5% at 0.2, 1, and 4 ng/mL fentanyl, respectively.
LC/MS assay of norfentanyl used an Agilent (Palo Alto, CA) 1100 LC-MSD equipped with a ZORBAX Eclipse XDB-C18 LC/MS (2.1 x 50 mm, 5µm) analytical column and an Eclipse XDB-C8 (2.1 x 12.5 mm, 5 µm) guard column (Agilent, Palo Alto, CA). The mobile phase was 15% acetonitrile (0.05% TFA) (solvent A) and 85% water (0.05% TFA) (solvent B) at 0.25 mL/min for 1 minute and then increased to 35% A over 2.5 minutes, held at 35% for 1.5 minutes, increased to 45% over 1.5 minutes, held at 45% for 1.5 minutes, and then increased to 90% over 0.5 minutes and was maintained at 90% A for 1.5 minutes before decreasing back to 15% A over 0.5 minutes. The column was reequilibrated for 3 minutes. Injection volume was 15 µL. The mass spectrometer was operated in positive electrospray mode. Nitrogen-drying gas (9 L/min) temperature was 350°C, nebulizer pressure was 25 psig, and the capillary voltage was 3500 V. Detection used the selected ion mode for norfentanyl and d5-norfentanyl (m/z 233.1 and 238.1, respectively) and fentanyl and d5-fentanyl (m/z 337.1 and 342.1, respectively). Norfentanyl and fentanyl were analyzed with the fragmentor 70V and 90V, respectively. Selected ion monitoring (SIM) resolution was set to low for both groups. Retention time was 3.6 and 5.7 minutes for norfentanyl and fentanyl, respectively. Calibration curves were obtained by analyzing drug-free plasma with 0.1 to 25 ng/mL fentanyl and 0.05 to 15 ng/mL norfentanyl. Each subject's samples (placebo and quinidine pretreatments) were analyzed on the same day. Interday coefficients of variation were 6%, 7%, and 4% at 0.6, 2, and 8 ng/mL norfentanyl, respectively.
Data Analysis
Fentanyl and norfentanyl area under the plasma time-concentration time curves (AUC) during the measurement interval (0-8 h), maximum observed plasma concentration or pupil change (Cmax, maximum effect), and time to maximum plasma concentration or effect (tmax) were determined by noncompartmental analysis using WinNonlin (Pharsight, Palo Alto, CA). Concentration-effect data were analyzed by nonparametrically collapsing the hysteresis loops to determine the value of ke0, the first-order rate constant for transfer between plasma and the effect compartment,13 using the program ke0obj.b Plasma concentrations, pupil diameter changes, and VAS scores were evaluated by two-way repeated-measures analysis of variance followed by the Student-Newman-Keuls test for multiple comparisons using SigmaStat (SPSS, Chicago). Other variables were compared by paired t-tests. All results are reported as mean ± standard deviation (SD). Statistical significance was assigned at p < 0.05.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Plasma fentanyl and norfentanyl concentrations after oral fentanyl administration following placebo or quinidine pretreatment are shown in Figure 4. Quinidine significantly increased fentanyl concentrations during the absorptive phase and during elimination. tmax was shortened and Cmax and AUC were significantly increased, but there was no effect on fentanyl elimination half-life (Table III). Interindividual variability in oral fentanyl kinetics was substantial, with coefficients of variation of 47% to 53% in Cmax and AUC, despite weight-adjusted dosing. Plasma norfentanyl concentrations were increased by quinidine (Figure 4). The metabolite/parent drug AUC ratio was increased during the measurement period (AUC0-8), but the AUC
ratio was unchanged.
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Quinidine pretreatment significantly increased oral fentanyl effects, assessed by dark-adapted pupil diameter change versus baseline (Figure 5). Maximum miosis was significantly increased by quinidine, although the AUC for oral fentanyl miosis did not reach statistical significance due to the large variability (Table III). Quinidine did not significantly increase oral fentanyl subjective effects, based on subject self-assessment using VAS scores (Figure 6).
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Concentration-effect data for oral fentanyl are provided in Figures 7 and 8, with raw data shown in Figure 7 and a hysteresis plot shown in Figure 8. Although there was scatter in the concentration-effect relationship, a general sigmoidal log concentration-effect relationship is apparent. There was minimal counterclockwise hysteresis observed in the concentration-effect relationship (Figure 8), indicating minimal delay in transit from plasma to the effect compartment. The half-life for equilibration between plasma and the effect compartment concentrations (t1/2 ke0 for miosis) averaged 12 minutes. These data are consistent with the minimal delay in onset after IV fentanyl (Figure 1), as well as previous results showing a relatively rapid onset of fentanyl effect14,15 and a rapid (7 min) t1/2 ke0 for miosis, particularly compared with morphine.14,16 Although the hysteresis loop was shifted rightward and upward by quinidine pretreatment, commensurate with higher plasma fentanyl concentrations, there was no collapse of the ascending and descending limbs, which would have reflected enhanced brain entry of fentanyl. Quinidine did not significantly change fentanyl ke0 for miosis (Table III).
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Safety was assessed by quinidine effects on the QT interval, oxygen saturation as measured by pulse oximetry, and the incidence of nausea or emesis requiring therapeutic intervention. The average increase in uncorrected QT interval was 40 ± 30 msec, and the maximum increase in QT interval in any subject at any time point was 120 msec. These were well below the predefined safety criteria of a 50% increase above baseline. One subject had an oxygen saturation less than 94% and briefly received supplemental oxygen. Treatment of nausea and/or vomiting with ondansetron was required in 6 subjects in the IV fentanyl protocol (without ondansetron prophylaxis) and 1 subject in the oral fentanyl protocol (after ondansetron prophylaxis). All safety-related events were considered minor.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Quinidine inhibits CYP3A as well as certain transport proteins and hence might inhibit fentanyl intestinal metabolism and/or transepithelial transport. Fentanyl is metabolized by human intestinal microsomes, predominantly by CYP3A-catalyzed N-demethylation.17 While quinidine inhibition of first-pass CYP3A-catalyzed fentanyl metabolism might explain the apparent increase in bioavailability, there was no decrease in the norfentanyl/fentanyl concentration or AUC ratios in quinidine-pretreated subjects. Thus, it is unlikely that quinidine inhibition of first-pass CYP3A-mediated metabolism accounts for increased fentanyl bioavailability. This is consistent with the lack of quinidine effects on the first-pass metabolism of loperamide in humans.11 Another alternative is that quinidine might alter renal fentanyl transport and excretion. Nonetheless, this is unlikely since fentanyl is extensively metabolized, and there is minimal (approximately 5%) renal clearance of unchanged fentanyl.18 Thus, while the renal clearance of digoxin is significantly decreased by quinidine inhibition of P-gp,19 inhibition of renal fentanyl clearance is not a viable explanation for the effects of quinidine on oral fentanyl disposition. Rather, quinidine effects on oral fentanyl disposition support the hypothesis that fentanyl is a substrate for human gastrointestinal P-gp (or some other quinidine-inhibitable transporter) and that this transport activity is an important determinant of oral fentanyl absorption and apparent bioavailability. This is consistent with the 25-fold lower IC50 for quinidine inhibition of P-gp compared with CYP3A.20
The second major finding was that quinidine had less influence on fentanyl effects. Nonetheless, the results are not unambiguous. Quinidine increased IV fentanyl miosis AUC, although time-specific effects were unchanged. Maximal miosis was also unchanged, although a ceiling effect might have precluded further decreases in pupil diameter by quinidine. Quinidine altered the apparent miosis elimination rate after IV but not oral fentanyl. Quinidine did not significantly alter oral fentanyl plasma concentration-effect relationships (pharmacodynamics). The minimal influence of quinidine on fentanyl effects, exclusive of absorption, was unexpected. Indeed, the IV fentanyl protocol was performed first (and without blood sampling because an unambiguous potentiation of fentanyl miosis by quinidine was anticipated). We therefore reevaluated the quinidine-loperamide interaction, on which the present protocol was based, and considered that perhaps quinidine effects on loperamide were due to a greater effect on oral bioavailability than had been appreciated.11 Consequently, quinidine effects on oral fentanyl disposition and pharmacodynamics were evaluated. Quinidine had a minimal effect on fentanyl pharmacodynamics; rather, quinidine effects on oral fentanyl miosis were attributable primarily to increased plasma concentrations rather than on fentanyl brain penetration and blood-brain barrier fentanyl transport. Nonetheless, the possibility that some fentanyl uptake transporter could "mask" an inhibitory effect of quinidine on the efflux component cannot be excluded.
Lack of quinidine effects on fentanyl pharmacodynamics differs from previous results, suggesting a role for P-gp-mediated fentanyl transport in the brain. In bovine brain capillary endothelial cells, fentanyl uptake occurred by an active, carrier-mediated process; verapamil decreased fentanyl efflux; and fentanyl inhibited rhodamine 123 transport, suggesting that fentanyl was a P-gp substrate.6 Consistent with this hypothesis, the P-gp inhibitor cyclosporine significantly altered fentanyl pharmacodynamics in mice, evidenced by dose-dependent increases in analgesia without changes in fentanyl plasma concentrations and protein binding.8 Similarly, mice showed significantly increased sensitivity to fentanyl after treatment with the P-gp inhibitor PSC833.21 In P-gp knockout mice, fentanyl antinociception was increased twofold compared with wild-type mice.9 Nevertheless, there may be species differences in fentanyl transport by P-gp, consistent with known species differences in P-gp transport of other compounds.10,22 Furthermore, not all investigations have found concordant results. In a P-gp-expressing cell line (L-MDR1), fentanyl was thought not to be a P-gp substrate.7 Furthermore, in addition to brain endothelial cell P-gp-mediated fentanyl efflux, Henthorn et al6 reported that there is an active uptake transporter with a greater capacity for fentanyl than P-gp. Under basal conditions, there was net uptake rather than net efflux of fentanyl, and the inward transport process was said to predominate over efflux. The identity of the fentanyl uptake transporter in brain endothelium, as well as its susceptibility to quinidine, remains unknown.
Potential candidates for the intestinal (and brain) fentanyl transporter include P-gp, as well as other more recently identified proteins. The pK of fentanyl is 8.4, making it predominantly cationic at physiologic pH. Relatively unlikely alternative candidates to P-gp would be the multidrug resistance-associated proteins since they transport mainly anionic compounds.5,23 More likely might be one or more of the organic cation transporters, such as OCT1-3 and OCTN1-3.3,24 The OCT system transports several bioactive amines and nitrogen-containing xenobiotics, including morphine.3 In rats, OCT3, OCTN1, and OCTN2 mRNAs are found at moderate levels in intestine and/or brain.25 Little information is available regarding the effect of quinidine on these transporters, although the IC50 for quinidine inhibition of rat OCT1 and OCT2 is known (15 µM).26 Clearly, additional information is needed on the role of transporters in fentanyl intestinal absorption and brain access.
Lack of quinidine effects on fentanyl pharmacodynamics also differs from a previous human investigation that suggested a role for P-gp-mediated brain transport of loperamide.11 However, there may be pertinent differences between fentanyl and loperamide transport by P-gp, affecting their susceptibility to P-gp inhibition. Loperamide is an unambiguous P-gp substrate in vitro and in animals in vivo, and P-gp knockout mice show profound sensitivity to the opiate effects of loperamide.10,27 In the only direct comparison of loperamide and fentanyl transport, there was substantial loperamide transport in L-MDR1 cells expressing human P-gp, while fentanyl was a relatively poor P-gp substrate.7 Thus, fentanyl appears to be a substantially weaker P-gp substrate than loperamide. This may explain the apparent difference between quinidine effects on fentanyl and loperamide pharmacodynamics in humans.
Differences in quinidine effects on fentanyl absorption and pharmacodynamics may also relate to quinidine concentrations. Plasma quinidine concentrations may have been inadequate to inhibit brain P-gp activity and fentanyl brain access, but greater intestinal concentrations may have been sufficient to inhibit intestinal P-gp and enhance fentanyl absorption.28,29 This does not, however, explain why quinidine enhanced loperamide11 but not fentanyl brain access.
Whether quinidine is the optimal in vivo probe for determining P-gp participation in brain drug penetration remains unknown. Quinidine did decrease the slope of the loperamide CO2 response curve but also increased oral loperamide bioavailability and plasma concentrations.11 The conclusion that quinidine changed loperamide pharmacodynamics and that P-gp therefore mediates loperamide brain penetration was based on the observation that respiratory depression after quinidine-loperamide occurred (30-60 min) when loperamide concentrations were unchanged from placebo-loperamide. Nevertheless, the CO2 response slope returned to near baseline at the time (2 h) of maximally increased (approximately twofold) loperamide concentrations. Similarly, while quinidine increased oral loperamide plasma concentrations and miosis, changes in pharmacodynamics were not apparent.30 Further investigations of quinidine effects on brain P-gp in humans might further validate this probe.
There are some potential clinical implications of the participation of P-gp, or other intestinal transporters, in oral fentanyl disposition. Diet, food, and herbal preparations such as grapefruit juice, orange juice, and St. John's wort affect P-gp activity31 and may influence oral fentanyl disposition and hence contribute to interindividual variability in dose-response relationships. There may be even more profound interactions than with the moderate effect of quinidine, for example, with P-gp induction or inhibition by HIV/AIDS drugs.32,33 Pharmacogenetic variability may also potentially contribute to interindividual variability in fentanyl disposition.34 While fentanyl is not commonly used orally, oral transmucosal fentanyl citrate (OTFC) is widely used in pain treatment.35 The OTFC lozenge is designed for rubbing on buccal mucosa and transmucosal drug absorption, but only a small portion (25%) is absorbed buccally. A significant portion (75%) is swallowed, absorbed intestinally, and subject to first-pass metabolism (two-thirds of the swallowed dose). Hence, half of the 50% overall bioavailability depends on intestinal absorption.36 In children, OTFC bioavailability is smaller and approximately equal to oral fentanyl bioavailability (30%), suggesting that a higher fraction of OTFC is swallowed and hence subject to factors affecting intestinal absorption.37 Further studies are needed to determine the influence of transporter pharmacogenetics and drug interactions on fentanyl disposition and dose-effect relationships.
In summary, this investigation showed that quinidine, used as an in vivo inhibitor probe for intestinal and brain P-gp, increased oral fentanyl absorption and hence clinical effect but had no major influence on fentanyl pharmacodynamics in humans. This suggests a role for P-gp in oral fentanyl intestinal disposition and a potential for P-gp-mediated drug interactions and pharmacogenetic variability, but the exact role for P-gp in brain fentanyl access requires further investigation.
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FOOTNOTES |
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Supported by an award from the National Institutes of Drug Abuse to the University of Washington Alcohol and Drug Abuse Institute, as well as by NIH grants K24-DA00417 (EDK) and M01-RR00037 (UW General Clinical Research Center). Presented in preliminary form at the annual meetings of the International Society for Anaesthetic Pharmacology (Orlando, FL 2002) and the American Society for Clinical Pharmacology and Therapeutics (Washington, DC, 2003).
a. A preliminary evaluation in 12 subjects showed no effect of ondansetron (4 mg IV) on dark-adapted pupil diameter. 
b. Written by Steve Shafer at Stanford University (available at http://anesthesia.stanford.edu/pkpd/, last accessed August 23, 2003).
Submitted for publication September 3, 2003; Revised version accepted November 27, 2003.
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REFERENCES |
|---|
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Levy G: Predicting effective drug concentrations for individual patients: determinants of pharmacodynamic variability. Clin Pharmacokinet 1998;34: 323-333.[CrossRef][Medline] [Order article via Infotrieve]
2. Fromm MF: P-glycoprotein: a defense mechanism limiting oral bioavailability and CNS accumulation of drugs. Int J Clin Pharmacol Ther 2000;38: 69-74.[Web of Science][Medline] [Order article via Infotrieve]
3. Lee G, Dallas S, Hong M, Bendayan R: Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 2001;53: 569-596.
4. De Boer AG, Van Der Sandt IC, Gaillard PJ: The role of drug transporters at the blood-brain barrier. Annu Rev Pharmacol Toxicol 2003;43: 629-656.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
5. Fricker G, Miller DS: Relevance of multidrug resistance proteins for intestinal drug absorption in vitro and in vivo. Pharmacol. Toxicol 2002;90: 5-13.[CrossRef][Medline] [Order article via Infotrieve]
6. Henthorn TK, Liu Y, Mahapatro M, Ng KY: Active transport of fentanyl by the blood-brain barrier. J Pharmacol Exp Ther 1999;289: 1084-1089.
7. Wandel C, Kim R, Wood M, Wood A: Interaction of morphine, fentanyl, sufentanil, alfentanil, and loperamide with the efflux drug transporter P-glycoprotein. Anesthesiology 2002;96: 913-920.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
8. Cirella VN, Pantuck CB, Lee YJ, Pantuck EJ: Effects of cyclosporine on anesthetic action. Anesth Analg 1987;66: 703-706.
9. Thompson SJ, Koszdin KK, Bernards CM: Opiate-induced analgesia as increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000;92: 1392-1399.[Web of Science][Medline] [Order article via Infotrieve]
10. Schinkel AH, Wagenaar E, Mol CA, van Deemter L: P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 1996;97: 2517-2524.[Web of Science][Medline] [Order article via Infotrieve]
11. Sadeque AJ, Wandel C, He H, Shah S, Wood AJ: Increased drug delivery to the brain by P-glycoprotein inhibition. Clin Pharmacol Ther 2000;68: 231-237.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
12. Phimmasone S, Kharasch ED: A pilot evaluation of alfentanil-induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans. Clin Pharmacol Ther 2001; 70: 505-517.[Web of Science][Medline] [Order article via Infotrieve]
13. Fuseau E, Sheiner LB: Simultaneous modeling of pharmacokinetics and pharmacodynamics with a nonparametric pharmacodynamic model. Clin Pharmacol Ther 1984;35: 733-741.[Web of Science][Medline] [Order article via Infotrieve]
14. Scott JC, Ponganis KV, Stanski DR: EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985;62: 234-241.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
15. Chapman CR, Hill HF, Saeger L, Gavrin J: Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain. Pain 1990;43: 47-55.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
16. Peng PWH, Sandler AN: A review of the use of fentanyl analgesia in the management of acute pain in adults. Anesthesiology 1999;90: 576-599.[Web of Science][Medline] [Order article via Infotrieve]
17. Labroo RB, Paine ME, Thummel KE, Kharasch ED: Fentanyl metabolism by human hepatic and intestinal cytochrome P450 3A4: implications for interindividual variability in disposition, efficacy and drug interactions. Drug Metab Dispos 1997;25: 1072-1080.
18. Mather LE: Clinical pharmacokinetics of fentanyl and its newer derivatives. Clin Pharmacokin 1983;8: 422-446.[Web of Science][Medline] [Order article via Infotrieve]
19. Hedman A, Angelin B, Arvidsson A, Dahlqvist R, Nilsson B: Interactions in the renal and biliary elimination of digoxin: stereoselective difference between quinine and quinidine. Clin Pharmacol Ther 1990;47: 20-26.[Web of Science][Medline] [Order article via Infotrieve]
20. Wandel C, Kim RB, Kajiji S, Guengerich P, Wilkinson GR, Wood AJ: P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies. Cancer Res 1999;59: 3944-3948.
21. Mayer U, Wagenaar E, Dorobek B, Beijnen JH, Borst P, Schinkel AH: Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J Clin Invest 1997;100: 2430-2436.[Web of Science][Medline] [Order article via Infotrieve]
22. Yamazaki M, Neway WE, Ohe T, Chen I, Rowe JF, Hochman JH, et al: In vitro substrate identification studies for P-glycoprotein-mediated transport: species difference and predictability of in vivo results. J Pharmacol Exp Ther 2001;296: 723-735.
23. Borst P, Evers R, Kool M, Wijnholds J: A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst 2000;92: 1295-1302.
24. Lamhonwah AM, Skaug J, Scherer SW, Tein I: A third human carnitine/organic cation transporter (OCTN3) as a candidate for the 5q31 Crohn's disease locus (IBD5). Biochem Biophys Res Commun 2003;301: 98-101.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
25. Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, Klaassen CD: Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos 2002;30: 212-219.
26. Arndt P, Volk C, Gorboulev V, Budiman T, Popp C, Ulzheimer-Teuber I, et al: Interaction of cations, anions, and weak base quinine with rat renal cation transporter rOCT2 compared with rOCT1. Am J Physiol Renal Physiol 2001;281: F454-68.
27. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, et al: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther 2001;299: 620-628.
28. Donahue JP, Dowdy D, Ratnam KK, Hulgan T, Price J, Unutmaz D, et al: Effects of nelfinavir and its M8 metabolite on lymphocyte P-glycoprotein activity during antiretroviral therapy. Clin Pharmacol Ther 2003;73: 78-86.[CrossRef][Medline] [Order article via Infotrieve]
29. Kharasch ED, Hoffer C, Whittington D, Sheffels P: Role of P-glycoprotein in the intestinal absorption and clinical effects of morphine. Clin Pharmacol Ther; in press.
30. Skarke C, Jarrar M, Schmidt H, Kauert G, Langer M, Geisslinger G, et al: Effects of ABCB1 (multidrug resistance transporter) gene mutations on disposition and central nervous effects of loperamide in healthy volunteers. Pharmacogenetics 2003;13: 651-660.[CrossRef][Medline] [Order article via Infotrieve]
31. Deferme S, Augustijns P: The effect of food components on the absorption of P-gp substrates: a review. J Pharm Pharmacol 2003;55: 153-162.[Medline] [Order article via Infotrieve]
32. Perloff MD, von Moltke LL, Greenblatt DJ: Fexofenadine transport in Caco-2 cells: inhibition with verapamil and ritonavir. J Clin Pharmacol 2002;42: 1269-1274.[Abstract]
33. de Maat MMR, Ekhart GC, Huitema ADR, Koks CHW, Mulder JW, Beijnen JH: Drug interactions between antiretroviral drugs and comedicated agents. Clin Pharmacokinet 2003;42: 223-282.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
34. Lin JH, Yamazaki M: Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 2003;42: 59-98.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
35. Payne R, Coluzzi P, Hart L, Simmonds M, Lyss A, Rauck R, et al: Long-term safety of oral transmucosal fentanyl citrate for breakthrough cancer pain. J Pain Symptom Manage 2001;22: 575-583.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
36. Streisand JB, Varvel JR, Stanski DR, Le Maire L, Ashburn MA, Hague BI, et al: Absorption and bioavailability of oral transmucosal fentanyl citrate. Anesthesiology 1991;75: 223-229.[Web of Science][Medline] [Order article via Infotrieve]
37. Wheeler M, Birmingham PK, Dsida RM, Wang Z, Cote CJ, Avram MJ: Uptake pharmacokinetics of the fentanyl Oralet in children scheduled for central venous access removal: implications for the timing of initiating painful procedures. Paediatr Anaesth 2002;12: 594-599.[CrossRef][Web of Science][Medline]
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, placebo; 
, quinidine); standard deviations are omitted for clarity. Asterisks denote significant differences between treatment groups (p < 0.05).
