Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 ...polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background: Nasal administration of opioids may be an alternative route to intravenous, subcutaneous, oral transmucosal, oral or rectal administration in some patients. Key features may be ...self‐administration, combined with rapid onset of action. The aim of this paper is to evaluate the present base of knowledge on this topic.
Methods: The review is based on human studies found in Medline or in the reference list of these papers. The physiology of the nasal mucosa and some pharmaceutical aspects of nasal administration are described. The design of each study is described, but not systematically evaluated.
Results: Pharmacokinetic studies in volunteers are reported for fentanyl, alfentanil, sufentanil, butorphanol, oxycodone and buprenorphine. Mean times for achieving maximum serum concentrations vary from 5 to 50 min, while mean figures for bioavailability vary from 46 to 71%. Fentanyl, pethidine and butorphanol have been studied for postoperative pain. Mean onset times vary from 12 to 22 min and times to peak effect from 24 to 60 min. There is considerable interindividual variation in pharmacokinetics and clinical outcome. This may partly be due to lack of optimization of nasal formulations. Patient‐controlled nasal analgesia is an effective alternative to intravenous PCA. Adverse effects are mainly those related to the opioids themselves, rather than to nasal administration. Some experience with nasal opioids in outpatients and for chronic pain has also been reported.
Conclusion: Nasal administration of opioids has promising features, but is still in its infancy. Adequately designed clinical studies are needed. Improvements of nasal sprayer devices and opioid formulations may improve clinical outcome.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Abstract
Prescription opioid diversion, abuse, addiction, and overdose are epidemic. Although unclear whether postoperative opioid prescribing is contributory, or how anesthesiologists and surgeons ...can contribute to a solution, nonetheless awareness and a research agenda are needed.
Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short‐term (2‐day) and steady‐state (2‐week) ...ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P‐glycoprotein (P‐gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration‐time curve (AUC)0–∞/dose ratio (ritonavir/control) for oral ALF 25‐fold. Steady‐state ritonavir increased the AUC0–∞/dose ratio for IV and oral ALF 4‐ and 10‐fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first‐pass CYP3A >96%. Chronic ritonavir inhibits hepatic CYP3A (>70%) and first‐pass CYP3A (>90%). Acute and steady‐state ritonavir increased the fexofenadine AUC0–∞ 2.8‐ and 1.4‐fold, respectively, suggesting P‐gp inhibition. Steady‐state compared with acute ritonavir caused mild apparent induction of P‐gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.
Clinical Pharmacology & Therapeutics (2008); 84, 4, 506–512 doi:10.1038/clpt.2008.102
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The synthetic opioid fentanyl undergoes extensive metabolism in humans. Systemic elimination occurs primarily by hepatic metabolism. When administered as a lozenge for oral transmucosal absorption, ...swallowed fentanyl is subject to first pass metabolism in the liver and possibly small intestine. Little is known, however, about the identity and formation of human fentanyl metabolites. This investigation identified routes of human liver microsomal fentanyl metabolism and their relative importance, tested the hypothesis that fentanyl is metabolized by human duodenal microsomes, and identified the predominantly responsible cytochrome P450 isoforms. A GC/MS assay using deuterated internal standards was developed for fentanyl metabolites. Piperidine N-dealkylation to norfentanyl was the predominant pathway of liver microsomal metabolism. Amide hydrolysis to despropionylfentanyl and alkyl hydroxylation to hydroxyfentanyl were comparatively minor pathways. Hydroxynorfentanyl was identified as a minor, secondary metabolite arising from N-dealkylation of hydroxyfentanyl. Liver microsomal norfentanyl formation was significantly inhibited by the mechanism-based P450 3A4 inhibitor troleandomycin and the P450 3A4 substrate and competitive inhibitor midazolam, and was significantly correlated with P450 3A4 protein content and catalytic activity. Of six expressed human P450 isoforms (P450s 1A2, 2B6, 2C9, 2D6, 2E1, and 3A4), only P450 3A4 exhibited significant fentanyl dealkylation to norfentanyl. These results indicate the predominant role of P450 3A4 in the primary route of hepatic fentanyl metabolism. Human duodenal microsomes also catalyzed fentanyl metabolism to norfentanyl; the average rate was approximately half that of hepatic metabolism. Rates of duodenal norfentanyl formation were diminished by troleandomycin and midazolam, and were significantly correlated with P450 3A4 activity, suggesting a prominent role for P450 3A4. These results demonstrate that human intestinal as well as liver microsomes catalyze fentanyl metabolism, and N-dealkylation by P450 3A4 is the predominant route in both organs. The fraction of fentanyl lozenge that is swallowed likely undergoes significant intestinal, as well as hepatic, first-pass metabolism. Intestinal and hepatic first-pass metabolism, as well as systemic metabolism, may be subject to individual variability in P450 3A4 expression and to drug interactions involving P450 3A4.
Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine are governed by CYP2D6 activity. Polymorphisms are ...a major cause of CYP2D6 variability. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for codeine based on CYP2D6 genotype. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for CYP2D6 genotype and codeine therapy.
Clinical Pharmacology & Therapeutics (2014); 95 4, 376–382. doi:10.1038/clpt.2013.254
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
CYP2D6
and
CYP2C19
polymorphisms affect the exposure, efficacy and safety of tricyclic antidepressants (TCAs), with some drugs being affected by CYP2D6 only (e.g., nortriptyline and desipramine) and ...others by both polymorphic enzymes (e.g., amitriptyline, clomipramine, doxepin, imipramine, and trimipramine). Evidence is presented for
CYP2D6
and
CYP2C19
genotype-directed dosing of TCAs. This document is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for
CYP2D6
and
CYP2C19
Genotypes and Dosing of Tricyclic Antidepressants.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The mechanism of individual variability in the fentanyl dose‐effect relationship is unknown. The efflux pump P‐glycoprotein (P‐gp) regulates brain access and intestinal absorption of numerous drugs. ...Evidence exists that fentanyl is a P‐gp substrate in vitro, and P‐gp affects fentanyl analgesia in animals. However, the role of P‐gp in human fentanyl disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous fentanyl are greater after inhibition of intestinal and brain P‐gp, using the P‐gp inhibitor quinidine as an in vivo probe. Two randomized, double‐blind, placebo‐controlled, balanced, two‐period crossover studies were conducted in normal healthy volunteers (6 males and 6 females) after obtaining informed consent. Pupil diameters and/or plasma concentrations of fentanyl and norfentanyl were evaluated after oral or intravenous fentanyl (2.5 μg/kg), dosed 1 hour after oral quinidine (600 mg) or placebo. Quinidine did not alter the magnitude or time to maximum miosis, time‐specific pupil diameter, or subjective self‐assessments after intravenous fentanyl but did increase the area under the curve (AUC) of miosis versus time (13.6 ± 5.3 vs. 8.7 ± 5.0 mm•h, p < 0.05) and decreased the effect of elimination (kel 0.35 ± 0.16 vs. 0.52 ± 0.24 h−1, p < 0.05). Quinidine increased oral fentanyl plasma Cmax (0.55 ± 0.19 vs. 0.21 ± 0.1 ng/mL) and AUC (1.9 ± 0.5 vs. 0.7 ± 0.3 ng•h•mL−1) (both p < 0.05) but had no effect on apparent elimination. Plasma norfentanyl/fentanyl AUC ratios were not diminished by quinidine. Quinidine significantly increased maximum miosis after oral fentanyl (3.4 ± 1.3 vs. 2.3 ± 1.3 mm, p < 0.05), commensurate with increases in plasma concentrations, but concentration‐effect relationships and the rate constant for the transfer between plasma and effect compartment (ke0) (1.9 ± 1.0 vs. 3.6 ± 2.6 h−1) were not significantly different. Quinidine increased oral fentanyl plasma concentrations, suggesting that intestinal P‐gp or some other quinidine‐sensitive transporter affects the absorption, bioavailability, and hence clinical effects of oral fentanyl. Quinidine had less effect on fentanyl pharmacodynamics, suggesting that if quinidine is an effective inhibitor of brain P‐gp, then P‐gp appears to have less effect on brain access of fentanyl.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Parecoxib is a parenteral cyclooxygenase-2 (COX-2) inhibitor intended for perioperative analgesia. It is an inactive prodrug hydrolyzed in vivo to the active inhibitor valdecoxib, a substrate for ...hepatic cytochrome P450 3A4 (CYP3A4); hence, a potential exists for metabolic interactions with other CYP3A substrates. This study determined the effects of parecoxib on the pharmacokinetics and pharmacodynamics of the CYP3A substrates fentanyl and alfentanil compared with the CYP3A inhibitor troleandomycin. Alfentanil is a low-extraction drug with a clearance that is highly susceptible to drug interactions; fentanyl is a high-extraction drug and, thus, is theoretically less vulnerable. We therefore also tested the hypothesis that the extraction ratio influences the consequence of altered hepatic metabolism of these opioids.
After Institutional Review Board-approved, written, informed consent was obtained, 12 22- to 40-yr-old healthy volunteers were enrolled in the study. The protocol was a randomized, double-blinded, balanced, placebo-controlled, three-session (placebo, parecoxib, or troleandomycin pretreatment) crossover. Subjects received both alfentanil (15 microg/kg) and fentanyl (5 microg/kg; 15-min intravenous infusion) 1 h after placebo, parecoxib (40 mg intravenously every 12 h), or troleandomycin (every 6 h). Study sessions were separated by 7 or more days. Opioid concentrations in venous blood were determined by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. Opioid effects were determined by pupillometry, respiratory rate, and Visual Analog Scale scores.
There were no significant differences between the placebo and parecoxib treatments in alfentanil or fentanyl plasma concentration, maximum observed plasma concentration, area under the plasma time-concentration time curve, clearance, elimination half-life, or volume of distribution. However, disposition of alfentanil, and to a lesser extent fentanyl, was significantly altered by troleandomycin. Clearances were reduced to 12% (0.64 +/- 0.25 ml. kg-1. min-1) and 61% (9.35 +/- 3.07) of control (5.53 +/- 2.16 and 15.3 +/- 5.0) for alfentanil and fentanyl (P < 0.001). Pupil diameter versus time curves were similar between placebo and parecoxib treatments but were significantly different after troleandomycin.
Single-dose parecoxib does not alter fentanyl or alfentanil disposition or clinical effects and does not appear to cause significant CYP3A drug interactions. CYP3A inhibition decreases alfentanil clearance more than fentanyl clearance, confirming that the extraction ratio influences the consequence of altered hepatic drug metabolism. Modified cassette, or "cocktail," dosing is useful for assessing drug interactions in humans.
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