Kinetics of intravenous and intramuscular morphine

Stanski, Donald R.; Greenblatt, David J.; Lowenstein, Edward

doi:10.1002/cpt197824152

Cited by 227 publications

(74 citation statements)

References 13 publications

(22 reference statements)

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“…Morphine is reported to have a high extraction ratio of 0.7 after intravenous administration in healthy volunteers 37. For a drug with a high extraction ratio, in general, hepatic blood flow is the rate‐limiting factor for drug elimination through the liver, which we confirmed in this study.…”

Section: Discussionsupporting

confidence: 82%

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

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Fukuda

Johnson

et al. 2016

CPT Pharmacom & Syst Pharma

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Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration‐time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age‐related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability.

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Section: Discussionsupporting

confidence: 82%

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Emoto

Fukuda

Johnson

et al. 2016

CPT Pharmacom & Syst Pharma

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“…In combination with mild preanesthetics and muscle paralysis, almost identical anesthetic regimens (70/30% N,O and morphine in doses equal to those used in the present study) have been shown to be fully adequate for abdominal surgery in humans (Stanski et al, 1978). If any environmentally related change in heart rate was observed, the anesthesia level was supplemented by sodium pentobarbital.…”

Section: Methodsmentioning

confidence: 78%

Functional anatomy of macaque striate cortex. I. Ocular dominance, binocular interactions, and baseline conditions

et al. 1988

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A series of experiments was carried out using 14C-2-deoxy-d-glucose (DG) in order to examine the functional architecture of macaque striate (primary visual) cortex. This paper describes the results of experiments on uptake during various baseline (or reference) conditions of visual stimulation (described below), and on differences in the functional architecture following monocular versus binocular viewing conditions. In binocular “baseline” experiments, monkeys were stimulated either (1) in the dark, (2) with a diffuse gray screen, or (3) with a very general visual stimulus composed of gratings of varied orientation and spatial frequency. In all of these conditions, DG uptake was found to be topographically uniform within all layers of parafoveal striate cortex. In monocular experiments that were otherwise similar, uptake was topographically uniform within the full extent of the eye dominance strip, in all layers. Certain other visual stimuli produce high uptake in the blobs, and still another set of visual stimuli (including high-spatial-frequency gratings) produce highest uptake between the blobs at parafoveal eccentricities, even in an unanesthetized, unparalyzed monkey. Eye movements per se had no obvious effect on striate DG uptake. Endogenous uptake in the blobs (relative to that in the interblobs) appears higher in the squirrel monkey than in the macaque. The pattern of DG uptake produced by binocular viewing was found to deviate in a number of ways from that expected by linearly summing the component monocular DG patterns. One of the most interesting deviations was an enhancement of the representation of visual field borders between stimuli differing from each other in texture, orientation, direction, etc. This “border enhancement” was confined to striate layers 1–3 (not appearing in any of the striate input layers), and it only appeared following binocular, but not monocular, viewing conditions. The border enhancement may be related to a suppression of DG uptake that occurs during binocular viewing conditions in layers 2 + 3 (and perhaps layers 1 and 4B), but not in layers 4Ca, 4Cb, 5 or 6. Another major class of binocular interaction was a spread of neural activity into the “unstimulated” ocular dominance strips following monocular stimulation. Such an effect was prominent in striate layer 4Ca, but it did not occur in layer 4Cb. This “binocular” spread of DG uptake into the inappropriate eye dominance strip in 4Ca may be related to the appearance of orientation tuning and orientation columns in that layer. No DG effects were seen that depended on the absolute disparity of visual stimuli in macaque striate cortex.

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“…or i.m. morphine in normal therapeutic doses are 80 ng/mL (38). In one comprehensive review (39), analgesia in cancer patients was associated with steady-state concentrations of morphine in plasma ranging from 6 to 364 ng/mL.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Singleton

Garcia

Moss

2008

Molecular Cancer Therapeutics

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Many patients with cancer receive combinations of drug treatments that include 5-fluorouracil (5-FU) and bevacizumab. Therapeutic doses of 5-FU are often associated with unwanted side effects, and bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that methylnaltrexone (MNTX), a peripheral antagonist of the M-opioid receptor, exerts a synergistic effect with 5-FU and bevacizumab on inhibition of vascular endothelial growth factor (VEGF) -induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC 50 of f100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC 50 of 5-FU from f5 Mmol/L to f7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC 50 of bevacizumab on inhibition of EC migration from f25 to f6 ng/mL. These synergistic effects were not observed with naltrexone, a tertiary M-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased receptor protein tyrosine phosphatase M activity, which was independent of M-opioid receptor expression. Silencing receptor protein tyrosine phosphatase M expression (small interfering RNA) in human EC inhibited both synergy between MNTX and bevacizumab or 5-FU and increased VEGF-induced tyrosine phosphorylation of Src and p190 RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory protein, RhoA, whereas silencing Src, Akt, or RhoA blocked VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of 5-FU and bevacizumab, which could improve index.

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Kinetics of intravenous and intramuscular morphine

Cited by 227 publications

References 13 publications

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

Functional anatomy of macaque striate cortex. I. Ocular dominance, binocular interactions, and baseline conditions

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

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