Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine

Skarke, Carsten; Jarrar, Marwan; Erb, Katharina; Schmidt, Helmut; Geißlinger, Gerd; Lötsch, Jörn

doi:10.1016/s0009-9236(03)00220-0

Cited by 61 publications

(44 citation statements)

References 21 publications

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“…Thus, the influence of frequent OPRM1 mutations on opioid pharmacodynamics was assessed in pooled data from 31 of these subjects (Table 1), who had participated in one or more previous studies, 3,4,12,13 with available plasma concentrations and pupil diameters after intravenous administration of morphine or M6G (Figure 1). In addition, to estimate the allelic frequency of the OPRM1 polymorphisms in a random sample of subjects, 279 unrelated volunteers were genotyped.…”

Section: Methodsmentioning

confidence: 99%

“…The subsequent analysis of functional consequences focused on OPRM1 polymorphisms found at a frequency of at least 5%, a value inspired by the frequency of functionally distinct cytochrome P450 2D6 phenotypes based on genetic polymorphisms. 18 Analysis of functional consequences of frequent OPRM1 mutations The plasma concentrations from the four previous studies 3,4,12,13 had all been analyzed by the same staff in the same laboratory on the same equipment using the same validated LC-MS/MS assay. 4 Addition of quality control samples and permanent stability tests of the analytes ensure the goodness of the validated method.…”

Section: Methodsmentioning

confidence: 99%

“…The intraday and interday variability was o10%. From studies involving the coadministration of other drugs along with the opioids, 12,13 only the data from the opioid-only condition were used in the present analysis.…”

Section: Methodsmentioning

confidence: 99%

“…The modeling process repeatedly employed goodness-offit procedures as follows: Two alternative models were applied to the data, (i) one model without inclusion of the genotype (or another parameter such as an interindividual variance assigned to a specific parameter, or sex assigned to a parameter to be tested for sex differences), and (ii) one Lötsch et al 4 Skarke et al 3 Skarke et al 12 Skarke et al 100% overlap with the IVS2 691C4G SNP. The 17C4T SNP was not found in the 31 subjects.…”

Section: Methodsmentioning

confidence: 99%

“…The purpose of the present assessment was to estimate which OPRM1 mutations in addition to the 118A4G SNP would merit a closer look for their consequences for clinical opioid therapy. The approach was to assess the allelic frequency of several OPRM1 polymorphisms in a greater random sample of subjects and to subsequently assess the functional role of those mutations that are found more frequently in a pooled data set of mitotic effects of morphine and M6G obtained in several previous studies 3,4,12,13 that focused on a single SNP or had a non-pharmacogenetic aim.…”

Section: Introductionmentioning

confidence: 99%

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Relevance of frequent μ-opioid receptor polymorphisms for opioid activity in healthy volunteers

Lötsch

Geißlinger

2006

Pharmacogenomics J

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Polymorphisms in the m-opioid receptor gene (OPRM1) are primary candidate sources of clinical variability in opioid therapy. Apart from the 118A4G single nucleotide polymorphism, nothing is known about the role of OPRM1 mutations in opioid therapy. The influence of the OPRM1 mutations on opioid pharmacodynamics was assessed in pooled data from 31 healthy volunteers obtained in previous studies with available plasma concentrations and pupil diameters after intravenous administration of morphine or morphine-6-glucuronide (M6G). A total of 24 candidate ORPM1 mutations were screened for and those found at an allelic frequency of at least 5% in the 31 subjects were analyzed for functional consequences, using population pharmacokinetic-pharmacodynamic modeling of the miotic effects of the opioids as a reliable and sensitive surrogate parameter of the central nervous opioid effects. Polymorphisms at an allelic frequency of X5% (n ¼ 310) were 118A4G in exon 1 (11.5%), the IVS2-31G4A (8.9%) and IVS2-691C4G (44.5%) SNPs in intron 2. The 118A4G SNP significantly increased the values of EC 50 by a factor of more than 2 (nonmutated: EC 50,morphine ¼ 30 nmol/l, EC 50,M6G ¼ 750 nmol/l, 118G carriers: EC 50,morphine ¼ 66 nmol/l, EC 50,M6G ¼ 1650 nmol/l), whereas the IVS2-691C4G SNP had no effect. Based on morphine and M6G, the present analysis encourages focusing on the 118A4G SNP when investigating the role of OPRM1 mutations for the activity of opioid analgesics. Other OPRM1 mutations are probably less important either owing to low allelic frequency or due to poor indications for functional consequences. This applies to opioid potency in the context of opioid therapy but not to pain processing or substance addiction, in which opioid receptors are involved but other or additional OPRM1 mutations may be important.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Relevance of frequent μ-opioid receptor polymorphisms for opioid activity in healthy volunteers

Lötsch

Geißlinger

2006

Pharmacogenomics J

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The mineralocorticoid receptor antagonist spironolactone enhances morphine antinociception

Lilius

Jokinen

Neuvonen

et al. 2013

European Journal of Pain

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Reply to: Letter to the Editor “Effect of Quinidine, a Strong P‐Glycoprotein Inhibitor, on the Pharmacokinetics and Central Nervous System Distribution of Naloxegol”

Al‐Huniti¹

2016

The Journal of Clinical Pharma

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Dear EditorWe thank Dr. Ruan for the letter to the editor regarding the potential impact of morphine and morphine-6-glucuronide (M6G), both of which are known P-glycoprotein (PGP) substrates, on the results and interpretation of our manuscript. We also thank you for providing us with the opportunity to respond to the letter.Dr. Ruan raised a very valid point in his letter about the potential increase in morphine-and M6G-induced miosis due to PGP inhibition by quinidine. Indeed, during the design phase of the study, we had considered and deliberated on the same point. Most commonly used μ-opioid agonists are substrates of PGP, and morphine was found to be a weak PGP substrate in vitro as well as in in situ animal studies. 1Morphine was selected in our study because published results had demonstrated that healthy human volunteers who received morphine intravenously did not experience enhanced pupillary effect when quinidine was coadministered. 2,3 In these published studies the profiles of the change in pupillary diameter with time were identical with and without quinidine coadministration, indicating that there was no change in the concentration-effect relationship.The active metabolite of morphine, M6G, is likely to have no effect in our study. The pupillary effect of the metabolite was found to be 22-fold less potent than that of morphine when M6G was dosed directly to healthy volunteers. 4 In our study plasma exposure of M6G (in terms of values for area under the curve) was less than 3-fold higher than that of morphine.Hence, based on published results that no change in morphine-induced miosis was seen when morphine (when dosed intravenously) was coadministered with quinidine, PGP inhibition of morphine and M6G did not affect pupillary results in our study, and we believe that our conclusion on the lack of effect of quinidine on the central nervous system distribution of naloxegol at therapeutic doses is appropriate. External Funding

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Respiratory and miotic effects of morphine in healthy volunteers when P-glycoprotein is blocked by quinidine

Abstract: Whereas morphine clearly produced miosis and respiratory depression, pretreatment with quinidine as an inhibitor of P-glycoprotein did not result in an enhancement of central nervous opioid effects in healthy volunteers.

Cited by 61 publications

References 21 publications

Relevance of frequent μ-opioid receptor polymorphisms for opioid activity in healthy volunteers

Relevance of frequent μ-opioid receptor polymorphisms for opioid activity in healthy volunteers

The mineralocorticoid receptor antagonist spironolactone enhances morphine antinociception

Reply to: Letter to the Editor “Effect of Quinidine, a Strong P‐Glycoprotein Inhibitor, on the Pharmacokinetics and Central Nervous System Distribution of Naloxegol”

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