Biomedical subjects

I Meineke

Publications and source records attributed to I Meineke.

At least 19 recordsLinked to original sources

PubMed2006

Genetic variation at the CYP2C locus and its association with torsemide biotransformation.

In 97 unselected volunteers and two additional homozygous carriers of CYP2C9(*)3, we investigated the oral clearance of torsemide in relation to 37 polymorphisms at the CYP2C gene locus. Torsemide total oral clearance was linearly associated with the number of CYP2C9(*)3 alleles (geometric mean: 59, 40 and 20 ml/min in carriers of no, one and two alleles) and so were the methyl- and ring-hydroxylation but not the carboxylation clearance. Haplotypes including the CYP2C9(*)3 allele were similarly associated with the clearances but no other variant and no haplotype not including the CYP2C9(*)3 variant. The extended haplotype length (EHL) of the CYP2C9 haplotypes was positively associated with higher activity of the gene product. Torsemide total oral clearance was predictable with r(2)=82.1% using plasma concentrations at 0.5, 1, 2 and 24 h. In conclusion, torsemide's biotransformation strongly depended on the CYP2C9(*)3 variant but no other. Higher clearance CYP2C9 haplotypes appear to be evolutionarily selected.

Adult↗

PubMed2005

Region specific distribution of levomepromazine in the human brain.

OBJECTIVE: The aim of this study was to examine concentrations of levomepromazine and its metabolite desmethyl-levomepromazine in different regions of human brain and in relationship to drug-free time. METHODS: Drug concentrations were measured in up to 43 regions of 5 postmortem human brains of patients previously treated with levomepromazine. To enable statistical comparison across brain regions several smaller brain areas were put together to form larger brain areas (cortex cerebri, limbic system, cerebellum, basal ganglia, thalamus). Mean values of drug concentrations in these larger brain areas were used in a repeated measurement ANOVA to analyze for region specific distribution. The elimination half-life in brain tissue was estimated with a NONMEM population kinetic analysis using the mean value of all brain regions of an individual case. RESULTS: Levomepromazine and desmethyl-levomepromazine appear to accumulate in human brain tissue relative to blood. Mean concentrations differed largely between individual brains, in part due to differences in dose of drug, duration of treatment and drug-free time before death. There was an apparent region-specific difference in levomepromazine concentrations with highest values in the basal ganglia (mean 316 ng/g) and lowest values in the cortex cerebri (mean 209 ng/g). The elimination half-life from brain tissue is longer than from blood and was calculated to be about one week. Similar results were obtained with desmethyl-levomepromazine. CONCLUSIONS: Levomepromazine shows a region-specific distribution in the human brain with highest values in the basal ganglia. This might be the consequence of low expression of the metabolic enzyme Cyp2D6 in the basal ganglia. If this finding is true also for other neuroleptic drugs it might increase our understanding of preferential toxicity of neuroleptic drugs against basal ganglia structures and higher volumes of basal ganglia of neuroleptic-treated patients. Furthermore, patients exposed to levomepromazine cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.

Aged↗

PubMed2002

Pharmacokinetics of doxepin and desmethyldoxepin: an evaluation with the population approach.

OBJECTIVE: Little information on the population pharmacokinetics of the tricyclic antidepressant doxepine and its pharmacologically active metabolite desmethyldoxepine is available. However, a more individualised drug therapy may be feasible if the influence of various patient characteristics on plasma concentration was known. PATIENTS AND METHODS: We retrospectively analysed pharmacokinetic therapeutic drug-monitoring data in 114 psychiatric patients (79 females, 35 males) treated with doxepine for a period of 22-306 days, mostly due to major depression. The data were analysed using the computer program NONMEM. For both, doxepine and its metabolite desmethyldoxepine, a one-compartment model was chosen. Pharmacokinetic parameters clearance (CL/F) and volume of distribution (V/F) of doxepine and desmethyldoxepine were modelled in terms of both random and fixed effects. RESULTS: The fit of the model to the concentration-time data was significantly improved when V/F was expressed as a function of weight ( P<0.05) and CL/F as a function of age ( P<0.05). Co-medication that inhibits P(450) isoenzymes lowered CL/F of doxepine by 15%. CONCLUSION: The analysis indicates that the factors age and, to some extent, body weight may be a guidance for individual doxepine dose regimens, which however needs confirmation in prospective clinical trials linking pharmacokinetics and therapeutic effect. Co-medication may represent only a minor important covariate.

Adult↗

PubMed2000

Measurement of free and bound malondialdehyde in plasma by high-performance liquid chromatography as the 2,4-dinitrophenylhydrazine derivative.

We established a method for the detection of free and total (free and bound) malondialdehyde (MDA) in human plasma samples after derivatisation with 2,4-dinitrophenylhydrazine (DNPH). Free MDA was prepared by perchloric acid deproteinisation whereas an alkaline hydrolysation step for 30 min at 60 degrees C was introduced prior to protein precipitation for the determination of total MDA. Derivatisation was accomplished in 10 min at room temperature subsequently chromatographed by HPLC on a reversed-phase 3 microm C(18) column with UV detection (310 nm). The detection limit was 25 pmol/ml for free and 0.3 nmol/ml for total MDA. The recovery of MDA added to different human plasma samples was 93.6% (n=11; RSD 7.1%) for the hydrolysation procedure. In samples from 12 healthy volunteers who underwent a hypoxic treatment (13% O2 for 6 h) we estimated a baseline value of total MDA of 2.16 nmol/ml (SD 0.29) (ambient air) with a significant increase to 2.92 (nmol/ml, SD 0.57; P=0.01) after the end of this physiological oxidative stress challenge. Plasma values of free MDA in these samples were close to our detection limit. The presented technique can easily performed with an isocratic HPLC apparatus and provides highly specific results for MDA as do sophisticated GC-MS methods.

Adolescent↗

PubMed2000

An add-in implementation of the RESAMPLING syntax under Microsoft EXCEL.

The RESAMPLING syntax defines a set of powerful commands, which allow the programming of probabilistic statistical models with few, easily memorized statements. This paper presents an implementation of the RESAMPLING syntax using Microsoft EXCEL with Microsoft WINDOWS(R) as a platform. Two examples are given to demonstrate typical applications of RESAMPLING in biomedicine. Details of the implementation with special emphasis on the programming environment are discussed at length. The add-in is available electronically to interested readers upon request. The use of the add-in facilitates numerical statistical analyses of data from within EXCEL in a comfortable way.

Aging↗

PubMed2000

A cell-kinetic model of CD34+ cell mobilization and harvest: development of a predictive algorithm for CD34+ cell yield in PBPC collections.

BACKGROUND: Mobilization and homing of PBPCs are still poorly understood. Thus, a sufficient algorithm for the prediction of PBPC yield in apheresis procedures does not yet exist. STUDY DESIGN AND METHODS: The decline of CD34+ cells in the peripheral blood during apheresis and their simultaneous increase in the collection bag were determined in a prospective study of 18 consecutive apheresis procedures. A cell-kinetic, four-compartment model describing these changes was developed. Retrospective data from 136 apheresis procedures served to further improve this model. A predictive algorithm for the yield was developed that considered the sex, weight, and height of the patient, the number of CD34+ cells in peripheral blood before apheresis, the inlet flow, and the duration of the apheresis. The accuracy of this algorithm was evaluated by comparison of the predicted and the observed yields of CD34+ cells in 105 prospective autologous and 148 retrospective allogeneic apheresis procedures. RESULTS: The correlation between predicted and observed yields was good for the autologous and allogeneic groups with a correlation coefficient (r) of 0.8979 and 0.8311 (p<0.0001), respectively. The regression is described by the equations log (measured value [m]) = 1.0118 + 0.8595 x log (predicted value [p]) for the autologous and log (m) = 2.226 + 0.7559 x log (p) for the allogeneic group. The respective equations for the zero-point regression are log (m) = 1.014 x log (p) and log (m) = 1.026 x log (p). The probability that the measured value was 90 percent or more of the predicted value was 83.8 percent for the autologous and 90.5 percent for the allogeneic apheresis procedures. CONCLUSION: The predictive accuracy of the algorithm and the slope of the zero-point regression curve were higher for allogeneic than autologous PBPC collections. The predictive algorithm may be a useful tool in PBPC harvest, enabling the adaptation of the size of the apheresis to the needs of each patient.

Algorithms↗

PubMed2000

Increased psychological responses and divergent neuroendocrine responses to m-CPP and ipsapirone in patients with panic disorder.

In patients with panic disorder and /or agoraphobia (PDA) an increased sensitivity of central 5-HT2C receptors and a decreased responsiveness of 5-HT1A receptors has been postulated. In the present study, neuroendocrine challenges were performed using oral doses of the non-selective 5-HT2C agonist m-chlorophenylpiperazine (m-CPP) (0.4 mg/kg), the selective 5-HT1A antagonist ipsapirone (0.3 mg/kg), and placebo in 40 patients with PDA and 12 healthy controls in order to compare 5-HT2C and 5-HT1A-specific psychobehavioural and neuroendocrine response patterns. At baseline, all psychobehavioural variables and the plasma concentration of noradrenaline (NE) were significantly increased in the patient group compared to the controls. The administration of m-CPP or ipsapirone was followed by comparable psychological symptoms and, in 55% of all patients, panic attacks. In comparison to the control subjects, patients were characterized by significantly higher psychological reactions to both challenge agents and a significantly higher NE response to m-CPP. In the patient group, there was also a trend towards an increased cortisol response after administration of m-CPP and a decreased cortisol and hypothermia response after administration of ipsapirone compared to the control group. The neuroendocrine findings of our study support earlier reports of opposite changes in the responsiveness of 5-HT2C and 5-HT1A-related receptors in PDA patients. The behavioural hypersensitivity to both, m-CPP and ipsapiron, shows that the provocation of anxiety and other psychological symptoms might be influenced by

Adolescent↗

PubMed1999

Population pharmacokinetics of piritramide in surgical patients.

BACKGROUND: Piritramide is a synthetic opioid used for postoperative analgesia in several European countries. The authors present a mixed-effects model of its population pharmacokinetics in patients undergoing surgery. METHODS: After institutional approval and informed patient consent was obtained, 29 patients who were classified as American Society of Anesthesiologists physical status I or II and aged 21-82 yr were enrolled in the study. They received 0.2 mg/kg piritramide as an intravenous bolus before anesthesia was induced. Central venous blood samples were drawn for as long as 48 h after administration of the drug. The plasma concentration of piritramide was determined by gas chromatography. The concentration-time data were analyzed by mixed-effects modeling. Target-controlled infusions and intermittent bolus regimens were simulated to identify a regimen suitable for patient-controlled analgesia based on population pharmacokinetics and published pharmacodynamic data. RESULTS: The pharmacokinetics of piritramide were described adequately by a linear three-compartment model. Patient age and weight were significant covariates. The values of the pharmacokinetic parameters are: V1 = 50.5 [1], V2 = 150 x (1 + 9.32 x 10(-3) x (age - 47 yr)) [l], V3 = 212 x (1 + 6.37 x 10(-3) x (age - 47 yr)) [l], Cl1 = 0.56 x (1 - 6.14 x 10(-3) x (age - 47 yr)) [l/min], Cl2 = 8.25 x (1 + 2.02 x 10(-2) x (Wt - 74 kg)) [l/min], Cl3 = 0.80 [l/min]. The age of 47 yr and the weight of 74 kg refer to the median values for these factors in the patients studied. Rapid distribution, slow distribution, and elimination half-lives for the median patient are 0.05, 1.34, and 10.43 h, respectively. The context-sensitive half-time after a 24-h infusion is predicted at 10.5 h in a 75-yr-old patient compared with 7 h for the median patient. CONCLUSIONS: Piritramide is distributed extensively and eliminated slowly. The pharmacokinetic profile of the drug allows for intermittent bolus administration even when constant effect compartment concentrations are desirable, e.g., for PLA.

Adult↗

PubMed1999

Persistence of haloperidol in human brain tissue.

OBJECTIVE: After discontinuation of neuroleptic drugs, their antipsychotic and antiparkinsonian effects are still present for a prolonged period. It is not known whether the extended effects of neuroleptic drugs in humans are due to the continued presence of drug in brain tissue or to long-lasting drug-induced physiologic changes. The aim of this study was to directly examine haloperidol concentrations in human brain tissue in relation to drug-free time. METHOD: Haloperidol concentrations were measured in five regions (temporal cortex, cingulate gyrus, caudate nucleus, dentate nucleus, corpus callosum) of the postmortem brains of 11 patients previously treated with haloperidol. Haloperidol was analyzed by means of high-performance liquid chromatography with ultraviolet detection. The half-life in brain tissue was estimated by a population kinetic analysis. RESULTS: Haloperidol concentrations in the human brain tissue were 10-30 times higher than optimal serum concentrations used in the treatment of schizophrenia. Haloperidol concentrations appeared to be homogeneously distributed across different brain areas within a single patient. There was no apparent relation between duration of treatment and mean haloperidol concentration. Higher doses of haloperidol seemed to be related to higher concentrations in brain tissue. The elimination half-life from brain tissue was calculated to be 6.8 days. CONCLUSIONS: The results may have implications for clinical treatment decisions and the design of clinical research protocols. Patients exposed to haloperidol cannot be considered to be free of residual effects of the drug for a number of weeks after withdrawal.

Antipsychotic Agents↗

PubMed1998

Assessment of drug accumulation in the evaluation of pharmacokinetic data.

The evaluation of drug accumulation is approached from a practical point of view. Estimates of accumulation indices as obtained from standard estimators-AUC, peak levels, and trough levels (RAUAUC Rmax and Rmin, respectively)-are compared and differences analyzed. The estimators are based on the concentration-time curve characteristics area under the concentration-time curve (AUC), maximum concentration, and trough level. Simulated data are used for the analysis, both noise-free and with random error added. The data are based on pharmacokinetic parameters derived from a clinical study. The numerical procedures can be reproduced by the interested reader with little effort. It is shown empirically that if Rmin, > RAUC then simple kinetic behavior cannot be safely assumed, but accumulation is a complex function of time. Rmax as obtained from the data and an estimate of this value based on time to peak concentration (tmax) and apparent elimination rate constant (lambda(z)) after a single dose and at steady state can then be compared in an attempt to exclude time-dependent kinetics. This new numerical procedure can provide valuable and even pivotal information regarding the accumulation kinetics of a compound under investigation. Recommendations on how to use the available concentration-time information to the best advantage are presented. It is concluded that the assessment of drug accumulation should not be confined to the calculation of just one estimate, because the three estimators RAUC, Rmax. and Rmin reflect different aspects of accumulation. Moreover, all information about accumulation should be carefully analyzed in the clinical context. This way the relevant accumulation can be identified for safe and efficacious drug treatment.

Algorithms↗

PubMed1998

Modelling of residual variability in toxicokinetic studies with sparse sampling: the case of tetrahydronaphthalene.

The present study describes the kinetics of tetrahydronaphthalene in male and female rats (five animals per dose per sex) at three dose levels (15, 50, and 150 mg/kg daily). Plasma concentration measurements were performed in the course of a subacute toxicity study of 28 days duration in an enriched study design. Two blood samples per animal were taken at different time points after application at day 1 and 16 (150 mg/kg daily) and at day 3 and 18 (15 and 50 mg/kg daily), respectively. Tetrahydronaphthalene was assayed by gas chromatography-mass spectrometry (GC-MS) after extraction. The data of plasma concentration time were analysed using non-linear mixed effects modelling as implemented in NONMEM. The structural model with the best fit employed one compartment kinetics with instantaneous drug input. Interindividual variability in both k and V was found to be very small [k, 0.201 h(-1), 0.013; V, 16.19 (kg), 1.77; population mean and SE]. No unequivocal evidence of dose dependence could be found. The kinetic parameter with the highest extent of variability was the extent of bioavailability which showed an coefficient of variation (CV) of 96%. Both gender and dose had no influence on the variability. The present approach is concluded to offer more insight into the relationship between dose, concentration and effect and into factors which explain variability in kinetics without additional testing or additional animals. Proposals for a refined sampling schedule are made.

Animals↗

PubMed1998

Determination of 2-hydroxyphenylacetic acid (2HPAA) in urine after oral and parenteral administration of coumarin by gas-liquid chromatography with flame-ionization detection.

The urinary excretion of 2-hydroxyphenylacetic acid (2HPAA) was studied in human volunteers after oral and parenteral doses of coumarin. The presence of 2HPAA in the urine was confirmed by gas chromatography mass spectroscopy (GC MS). Mass spectra of reference material and samples are presented. The determination of 2HPAA was carried out by GC with flame-ionization detection. Prior to analysis samples were extracted into ethyl ether and the analytes were derivatized with trimethlyphenylammonium hydroxide. A calibration range from 0.3 to 150 micrograms ml-1 was established using 3-hydroxyphenyl acetic acid (3HPAA) as an internal standard. On average less than 10% of the coumarin administered were excreted into the urine in the form of 2HPAA.

Administration, Oral↗

PubMed1998

Influence of urine pH and urinary flow on the renal excretion of memantine.

AIMS: The present study assessed the influence of urinary flow rate and urine pH on the renal excretion of the NMDA-receptor antagonist memantine. METHODS: In a randomized, open, four-period cross-over trial, 12 healthy male volunteers received 10 mg memantine daily for 43 days. After reaching steady state conditions the volunteers were allocated to four different regimens to alter urine pH and urinary flow, which were each separated by a 1 week period while the study medication continued (A: acidification of urine pH, low urinary flow; B: acidification of urine pH, high urinary flow; C: alkalinization of urine pH, low urinary flow; D: alkalinization of urine pH, high urinary flow). RESULTS: The renal clearance of memantine (CL(R)) in regimen A and B was 7-10 fold higher in comparison with regimen C and D (P<0.05). There were small but statistically significant differences of CL(R) between the two regimens with acidic urine pH (A: median: 210.2 ml min(-1) vs B: median: 218.7 ml min(-1)) and between the two regimens with alkaline urine pH (C: median: 19.4 ml min(-1) vs D: median: 30.5 ml min(-1)). The amount of memantine excreted into the urine within one regimen (Ae0-24h) was 5.7-7.4 fold higher in regimens A and B than C and D (P< 0.05). Differences of the AUC(0,24 h) and Cmax/AUC(0,24 h) were significant (P<0.05) between each of the regimens with acidic urine pH (A, B) and regimens (C, D) with alkaline urine pH (A vs C, A vs D, B vs C, B vs D) but not between regimens A vs B or C vs D. CONCLUSIONS: The present study demonstrated a considerable effect of urine pH, whereas no clinically relevant change of the renal excretion of memantine with urinary flow could be detected. As the renal excretion of memantine may have an impact on therapeutic efficacy changes of dietary habits that may alter urine pH should be avoided during treatment with memantine.

Adult↗

PubMed1998

Routine measurement of fluoxetine and norfluoxetine by high-performance liquid chromatography with ultraviolet detection in patients under concomitant treatment with tricyclic antidepressants.

A robust and rapid high-performance liquid chromatography (HPLC) method is described for therapeutic drug monitoring of fluoxetine and norfluoxetine in the presence of six frequently-used tricyclic antidepressants and their respective metabolites. Liquid-liquid extraction into n-hexane/acetonitrile is used with reextraction into hydrochloric acid for clean-up. The chromatographic separation is carried out on a CN column. The minimum detectable amount is 3 ng injected on column. In addition to qualitative and quantitative validation data for the assay method, results from patient samples are presented. It is concluded that for patients treated with fluoxetine, therapeutic drug monitoring is valuable for optimizing the therapy.

Antidepressive Agents, Tricyclic↗

PubMed1997

Non-response to maprotiline caused by ultra-rapid metabolism that is different from CYP2D6?

CASE: We are reporting about a patient with major depression who failed to respond to pharmacotherapy due to ultra-rapid metabolism of maprotiline. Under daily oral doses of 175 mg maprotiline, the patient's metabolic ratio (MR) for maprotiline in plasma was 9.2 (expected MRp: 2.4) and the clearance of maprotiline (CLM) was 4190 ml.min-1 (expected CLM = 1220 in extensive metabolisers of CYP2D6). RESULTS: The patient's MRurine for sparteine was 0.5, which is within the range for extensive metabolisers of CYP2D6. Genotyping did not show a duplication of the CYP2D6L allele. The patient's caffeine half-life was 10 h, thus, precluding ultra-rapid metabolism for CYP1A2. The therapeutic regiment was changed to co-administration of 200 mg maprotiline and 20 mg fluoxetine once per day in order to inhibit metabolism via CYP2D6. Subsequently, MRP of maprotiline (4.9) and CLM were reduced (1900 ml.min-1; expected CLM in poor metabolisers: of CYP2D6 364). This regimen improved the clinical outcome of the underlying disease. CONCLUSION: We conclude that for the non-response seen with maprotiline, P450 isozymes other than CYP2D6 or CYP1A2 are responsible. As CYP2C19 is involved in the metabolism of a number of tricyclic antidepressants it may be a candidate for ultra-rapid metabolism in this patient.

Alleles↗

PubMed1997

Pharmacokinetics and pharmacodynamics of candesartan after administration of its pro-drug candesartan cilexetil in patients with mild to moderate essential hypertension--a population analysis.

OBJECTIVE: The pharmacokinetics and pharmacodynamics of the angiotensin (AT) II receptor, AT1-subtype, antagonist candesartan were investigated in a dose-finding study in 232 patients of either gender, aged 28-69 years and weighing 54-110 kg. The study was a double-blind, placebo-controlled trial in which oral doses of 2, 4, 8, 12 and 16 mg once daily were given as the pro-drug candesartan cilexetil from day 0 to day 28. RESULTS: The population pharmacokinetics of candesartan could be best described by a two-compartment body model, parameterized in terms of clearance (14.1 1.h-1), central volume of distribution (118 1), peripheral volume (272 1) and intercompartmental clearance (15.4 1.h-1). From these model parameters, a cumulation half-life (t1/2, beta) of 29 h was derived. Age and weight were influencing factors for the distribution and elimination of the drug. Systolic and diastolic blood pressure were lowered by the treatment in a dose-dependent fashion. The maximum effect of each dose was reached after repeated administration. The link between plasma concentrations and effect could be described by a linear model when trough concentrations and blood pressure, measured at the same time, were modelled. In this model, the time dependence is implicitly handled as the trough concentrations increased during repeated administration. After treatment with the highest dose used in the trial (16 mg), the population estimate for the diastolic blood pressure was reduced from 103.2 mmHg (pre-dose day 0) to 93.3 mmHg (on day 29) and the systolic blood pressure from 154.6 mmHg (pre-dose day 0) to 137.9 mmHg (on day 29). None of the covariates (age, weight, gender) had an influence on the concentration-effect relationship.

Adult↗

PubMed1997

Modelling of non-linear pharmacokinetics in sheep after short-term infusion of cardiotoxic doses of imipramine.

Imipramine was administered to sheep (n = 10) by intravenous infusion in high doses (450 mg-900 mg) to elicit cardiovascular shock. A cardiac assist device was then employed to manage the acute overdose situation. The concentration-time course of imipramine and its metabolite desmethylimipramine in plasma was measured by HPLC. As an indicator of imipramine's cardiotoxic effect, cardiac output was monitored. The aim of the study was to evaluate the pharmacokinetics under these conditions and to assess the efficiency of a cardiac assist device with (n = 5) and without (n = 5) an integrated haemoperfusion unit in removing drug from the circulation. The kinetics of imipramine could be described by a three compartment body model with concentration-dependent clearance resulting in non-linear kinetics. The changes in cardiac output with time could be linked to the pharmacokinetic model by a linear relationship. The cardiac assist device was found to contribute to the overall elimination of imipramine whereas the haemoperfusion unit had no clinically relevant impact.

Animals↗

PubMed1996

Morphine-6-O-beta-D-glucuronide but not morphine-3-O-beta-D-glucuronide binds to mu-, delta- and kappa- specific opioid binding sites in cerebral membranes.

We investigated the nature of interaction of morphine-3-O-beta-D-glucuronide (M3G) and morphine-6-O-beta-D-glucuronide (M6G) with opioid binding sites at the mu-, delta- and kappa-opioid receptors (mu-OR, delta-OR and kappa-OR) in cerebral membranes. Saturation binding experiments revealed a competitive interaction of M6G with all three opioid receptors. Inhibition binding experiments at the mu-OR employing combinations of morphine and M6G resulted in a rightward shift of the IC50 for morphine proportional to the M6G concentration, thus strengthening the finding of competitive interaction of M6G at the mu-opioid binding site. Data in absence and presence of M6G were included in a three-dimensional model. Compared to a model with one binding site a model with two binding sites significantly improved the fits. This might indicate that different mu-OR subtypes are involved. Hydrolysis of M6G to morphine was investigated and did not occur. Therefore the effects of M6G on binding to the mu-OR were due to M6G and not due to morphine. In contrast, M3G at the three opioid receptors was found to inhibit binding being about 300 times weaker than morphine. This effect was well explained by the amount of contaminating morphine (about 0.3%) identified by HPLC. We conclude that M6G binds to mu-, delta- and kappa-OR in a competitive manner. Some of our results on the mu-OR suggest two binding sites for agonists at the mu-OR and that M6G binds to both sites. Our results suggest that the high potency of M6G as an analgesic is mediated through opioid receptors. In contrast, M3G does not interact with the mu-, delta- or kappa-OR. We therefore doubt that any effect of M3G is mediated via opioid receptors.

Animals↗