Role of P‐glycoprotein in clinical effects of morphine, fentanyl and methadone

Kharasch, Evan D.; Whittington, Dale; Altuntas, T. Gul; Sheffels, Pamela; Hoffer, Christine

doi:10.1016/s0009-9236(03)90419-x

Cited by 7 publications

(12 citation statements)

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“…[11][12][13][14] It was reported that the inhibition of intestinal P-glycoprotein by oral administration of quinidine enhances the absorption and pharmacological effect of morphine in humans. 15) Oral administration of quinidine also elevated the antinociception of orally-administered morphine in rats. Grapefruit juice extracts cause a four-fold increase in the transport of [ 3 H]vinblastine, a P-glycoprotein substrate, from apical to basolateral sides across human intestinal Caco-2 cells.…”

Section: Resultsmentioning

confidence: 95%

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Enhancement by Grapefruit Juice of Morphine Antinociception

Okura

Ozawa

Ito

et al. 2008

Biological & Pharmaceutical Bulletin

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The aim of this study was to investigate the effect of grapefruit juice intake on the antinociception of morphine in rats. The antinociception of morphine (30 mg/kg, per os (p.o.)) was significantly enhanced by the oral administration of grapefruit juice (2 ml/rat). Further, the effect of grapefruit juice was examined in morphinetolerant rats. The repeated administration of morphine (100 mg/kg p.o.) for 5 d caused a marked decrease in the antinociception, indicating the development of morphine-tolerance. In the morphine-tolerant rats, oral administration of grapefruit juice potentiated significantly the antinociceptive effect of morphine. To examine the pharmacokinetics of morphine after the repeated treatment with morphine for 5 d, microdialysis probes were implanted into the jugular vein and spinal intrathecal space in rats. The morphine concentrations in the blood and intrathecal cerebrospinal fluid (CSF) were gradually decreased by the repeated treatment with morphine. The grapefruit juice treatment significantly increased the blood concentration of morphine in morphine-tolerant rats. These results suggest that oral administration of grapefruit juice enhances the morphine antinociception by increasing the intestinal absorption of this agent.

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Section: Resultsmentioning

confidence: 95%

“…[12][13][14] In humans, it has been reported that the absorption of morphine is regulated by intestinal P-glycoprotein. 15) Further, P-glycoprotein may be partially associated with morphine tolerance.…”

mentioning

confidence: 99%

Enhancement by Grapefruit Juice of Morphine Antinociception

Okura

Ozawa

Ito

et al. 2008

Biological & Pharmaceutical Bulletin

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“…P-glycoprotein mediates the efflux of morphine and affects the intestinal absorption of morphine in humans. 4) Thus the effects of morphine administration on P-glycoproteinmediated transport was characterized in Caco-2 cells using Since the accumulation was restored to the control level by the addition of cyclosporin A, it is suggested that the decrease in [ 3 H]vincristine accumulation is due to the stimulatory effects on P-glycoprotein-mediated efflux. The accumulation of rhodamine123 was also decreased after culture with morphine, and the efflux of rhodamine123 from Caco-2 cells was significantly increased after culture with morphine.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, P-glycoprotein (ABCB1, an MDR1 gene product), a drug resistance-related transporter, affects the intestinal absorption of morphine in humans and the distribution of morphine in the brain in mice and rats. [4][5][6][7][8] Aquilante et al reported that repeated morphine administration caused a two-fold increase in the level of P-glycoprotein in the rat brain associated with a decrease in the antinociceptive effects. 9) King et al also reported that an antisense-oligo against mdr1a suppressed the development of antinociceptive tolerance to intracerebroventricularly administered morphine.…”

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confidence: 99%

“…11) In patients treated with a sustained-release dosage form of morphine, P-glycoprotein in the intestine is more significantly affected than that at the blood-brain barrier, since the intestinal epithelium might be exposed to a relatively high concentration of morphine in a sustained manner. It was reported that intestinal Pglycoprotein affects morphine absorption in humans 4) and rats. 12,13) The previous studies led to the assumption that repeated treatment with morphine causes an increase in intestinal P-glycoprotein-mediated transport, subsequently leading to a decrease in the oral bioavailability of this drug.…”

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Effects of Repeated Morphine Treatment on the Antinociceptive Effects, Intestinal Absorption, and Efflux from Intestinal Epithelial Cells of Morphine

Okura

Ozawa

Ibe

et al. 2009

Biological & Pharmaceutical Bulletin

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The present study was conducted to investigate the effects of repeated treatment with morphine on the drug's antinociceptive effects, intestinal absorption, and transepithelial transport. The antinociceptive effects of morphine in rats were markedly decreased after repeated oral administration of the drug for 5 d, indicating the development of tolerance. In the morphine-tolerant rats, intestinal absorption of morphine was determined using the in situ loop method. Absorption of morphine from the jejunum was significantly decreased after repeated administration. The permeability of human intestinal epithelial Caco-2 cells was increased in the efflux direction after repeated treatment. The repeated administration of morphine also reduced the cellular accumulation and efflux of P-glycoprotein substrates ([ 3 H]vincristine and rhodamine123) from Caco-2 cells, suggesting that it enhances P-glycoprotein-mediated efflux in Caco-2 cells. These results suggest that repeated use enhances the efflux of morphine in the epithelial cells of the small intestine, subsequently decreasing its intestinal absorption.

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Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6

Cox

Bumpus

2016

ChemMedChem

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Previously, we observed that the oxazinone ring is important for CYP2B6 activity toward efavirenz ((4S)-6-Chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one), a CYP2B6 substrate used to treat HIV. Here, to further understand the structural characteristics of efavirenz that render it a CYP2B6 substrate, we test the importance of each heteroatom of the oxazinone ring. We assembled a panel of five analogues: 6-Chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-2-methyl-4-(trifluoromethyl)-2H-3,1-benzoxazine (1), (4S)-6-Chloro-4-[(1E)-2-cyclopropylethenyl]-3,4-dihydro-4-(trifluoromethyl)-,2(1H)-quinazolinone (2), (4S)-6-Chloro-4-(2-cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (3), 6-Chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinolinone (4), and 6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]dioxin-2-one (5). Metabolism of 1–5 was investigated using human liver microsomes, individual P450s, and mass spectrometry or UV absorbance detection. Steady-state analysis of CYP2B6 metabolism of 1–5 showed KM values ranging from 0.3 to 3.9 fold different than observed for efavirenz (KM of 3.6 ± 1.7 μM). The lowest KM values approximating 1 μM, were observed for metabolism of 1, while the largest KM, 14 ± 6.4 μM, was found for 4. Our work reveals that analogues with heteroatom changes in the oxazinone ring are still CYP2B6 substrates, though the changes KM suggest altered substrate binding.

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Role of P‐glycoprotein in clinical effects of morphine, fentanyl and methadone

Abstract: Clinical Pharmacology & Therapeutics (2003) 73, P17–P17; doi:

Cited by 7 publications

References 0 publications

Enhancement by Grapefruit Juice of Morphine Antinociception

Enhancement by Grapefruit Juice of Morphine Antinociception

Effects of Repeated Morphine Treatment on the Antinociceptive Effects, Intestinal Absorption, and Efflux from Intestinal Epithelial Cells of Morphine

Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6

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