Altered expression of MRP2, MRP3 and UGT2B1 in the liver affects the disposition of morphine and its glucuronide conjugate in a rat model of cholestasis

Objectives The aim was to investigate the disposition of morphine and morphine‐3‐glucuronide (M3G) in a rat model of cholestasis induced by bile duct ligation (BDL). Methods Morphine (15 mg/kg) was administered intravenously, and morphine and M3G concentrations in the plasma and urine measured by HPLC. Changes in the mRNA expression of multidrug resistance‐associated protein (MRP)2, MRP3 and UDP‐glucuronosyltransferase (UGT)2B1 in the liver were estimated using RT‐PCR. Key findings Although the plasma morphine concentrations declined exponentially, the elimination was delayed 3 and 5 days after BDL. Plasma M3G concentrations on day 1 after BDL were similar to those in the untreated control group, but were increased 3 and 5 days after BDL. Expression of MRP3 and UGT2B1 mRNA increased after BDL. The urinary excretion of M3G was increased significantly after BDL. Conclusions Enhanced glucuronidation of morphine and transportation of M3G into the blood increased the plasma M3G concentration in the BDL groups. However, M3G disposition 1 day after BDL was similar to that in the untreated control group because urinary excretion of M3G increased.     

Detection and identification of 2‐nitro‐morphine and 2‐nitro‐morphine‐6‐glucuronide in nitrite adulterated urine specimens containing morphine and its glucuronides

In vitro urine adulteration is a well‐documented practice adopted by individuals aiming to evade detection of drug use, when required to undergo mandatory sports and workplace drug testing. Potassium nitrite is an effective urine adulterant due to its oxidizing potential, and has been shown to mask the presence of many drugs of abuse. However, limited research has been conducted to understand its mechanism of action, and to explore the possibility of the drugs undergoing direct oxidation to form stable reaction products. In this study, opiates including morphine, codeine, morphine‐3‐glucuronide and morphine‐6‐glucuronide were exposed to potassium nitrite in water and urine to mimic the process of nitrite adulteration. It was found that two stable reaction products were detected by liquid chromatography‐mass spectrometry (LC‐MS) when morphine and morphine‐6‐glucuronide were exposed to nitrite. Isolation and elucidation using spectrometric and spectroscopic techniques revealed that they were 2‐nitro‐morphine and 2‐nitro‐morphine‐6‐glucuronide, respectively. These reaction products were also formed when an authentic morphine‐positive urine specimen was fortified with nitrite. 2‐Nitro‐morphine was found to be stable enough to undergo the enzymatic hydrolysis procedure and also detectable by gas chromatography‐mass spectrometry (GC‐MS) after forming a trimethylsilyl derivative. On the contrary, morphine‐3‐glucuronide did not appear to be chemically manipulated when exposed to potassium nitrite in urine. These reaction products are not endogenously produced, are relatively stable and can be monitored with both LC‐MS and GC‐MS confirmatory techniques. As a result, these findings have revealed the possibility for the use of 2‐nitro‐morphine and 2‐nitro‐morphine‐6‐glucuronide as markers for the indirect monitoring of morphine and morphine‐6‐glucuronide in urine specimens adulterated with nitrite. Copyright © 2013 John Wiley & Sons, Ltd.     

Pharmacokinetic and pharmacodynamic study of morphine and morphine 6‐glucuronide after oral and intravenous administration of morphine in children with cancer

The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of morphine and morphine 6‐glucuronide (M6G) in children with cancer. Serum concentrations of morphine and M6G in children who received single oral or short term continuous intravenous morphine were determined by HPLC and ELISA assays, respectively. The serum C_max of morphine and M6G after i.v. morphine administration was 560.5 and 309.0 nM and the T_max was 61 and 65 min, respectively. The elimination half‐life was 140.0 and 328.7 min, respectively. After oral administration of morphine, the serum C_max of morphine and M6G was 408.34 and 256.3 nM and the T_max was 40.0 and 60 min, respectively. The half‐life was 131.0 and 325.8 min, respectively. The side effects were: drowsiness (100%), nausea and/or vomiting (57%), pruritus (28%) and urinary retention (14%). There were no reports of respiratory complications. This study showed that pharmacokinetics factors of morphine and M6G in children were significantly different from adults. Therefore the required dose for children should be different from that of adults and should be based on studies performed on children rather than on studies on adults. Some adverse effects, particularly nausea and pruritus, may be commoner than is usually thought, while others, particularly respiratory problems did not occur. Copyright © 2009 John Wiley & Sons, Ltd.     

The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine

AIMS: To investigate the pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c. i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine. METHODS: Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G. RESULTS: After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l- 1, for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median tmax values for morphine and M3G were significantly longer than after i.v. morphine (P< 0.001 and P< 0.05, respectively), with a trend to a longer tmax for M6G (P = 0. 09). The appearance half-lives after s.c.b. morphine for M6G and M3G were also significantly longer than after i.v. morphine (P = 0.03 and P< 0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with significantly longer median tmax values for morphine (P< 0.001), M6G (P< 0.001) and M3G (P< 0.05), and the mean standardized Cmax values significantly lower than after both i.v. and s.c.b. morphine (morphine P< 0.001, M6G P< 0.001 and M3G P< 0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (log-transformed AUC ratio 0.78, 90% CI 0.66-0.93), M6G (0.72, 90% CI 0.63-0.82), or M3G (0.65, 90% CI 0.54-0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study. CONCLUSIONS: Although bioequivalence was demonstrated between the s. c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were significantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.     

Synthesis of morphine‐[N‐methyl‐14C]‐6‐β‐D‐glucuronide

Protected morphine‐6‐glucuronide was converted into morphine‐[N‐methyl‐¹⁴C]‐6‐glucuronide by a three‐step procedure. Methyl (3‐pivaloylmorphin‐6‐yl 2,3,4‐tri‐O‐isobutyryl‐β‐D‐glucopyranosid)uronate was N‐demethylated by treatment with 1‐chloroethyl chloroformate to afford protected normorphine‐6‐glucuronide as its hydrochloride salt. The normorphine‐6‐glucuronide derivative was alkylated with iodomethane‐[¹⁴C] in the presence of potassium carbonate to produce C‐14 labelled protected morphine‐6‐glucuronide. Finally, hydrolysis of the protecting groups using 5% sodium hydroxide solution gave morphine‐[N‐methyl‐¹⁴C]‐6‐β‐D‐glucuronide with a specific activity of 41.8 mCi mmol^?1 and radiochemical purity of 99.2% (HPLC). Copyright © 2002 John Wiley & Sons, Ltd.     

Comparative pharmacokinetic study of paclitaxel and docetaxel in streptozotocin‐induced diabetic rats

The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P‐glycoprotein (P‐gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C_max of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P‐gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P‐gp and Cyp3A between the two taxanes. Copyright © 2012 John Wiley & Sons, Ltd.     

No significant influence of OCT1 genotypes on the pharmacokinetics of morphine in adult surgical patients

We investigated the impact of genetic variants in OCT1 (SLC22A1) on morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) pharmacokinetics in adult patients scheduled for major surgery. Blood samples were taken before and 5, 10, 15, 30, 45, 60 and 90 min after a bolus of morphine (0.15 mg/kg). Patients were genotyped for the genetic variants (rs12208357, rs34059508, rs72552763 and rs34130495) in OCT1. Eighty-six patients completed the trial. The mean difference (95% confidence interval) for dose adjusted morphine, M3G and M6G AUC was 0.9 (?0.7–2.4), ?5.9 (?11.8 to ?0.03) and ?1.1 (?2.5–0.4) h/L*10^?6, respectively, in patients with two reduced function alleles compared to patients with no reduced function alleles in OCT1. Accordingly, the (AUC_M3G/Dose)/(AUC_{morphine/Dose}) and (AUC_M6G/Dose)/(AUC_{morphine/Dose}) ratio was reduced, ?1.8 (?3.2 to ?0.4) and ?0.4 (?0.7 to ?0.03), respectively, when comparing the same groups. OCT1 variants had no influence on the experience of pain, adverse events or the number of PCA doses used. In conclusion, genetic variants in OCT1 had a small and clinically unimportant impact on the exposure of morphine after intravenous administration. Our results do not support pre-emptive genotyping for OCT1 prior to morphine administration in patients scheduled for major surgery.     

Postmortem tissue distribution of morphine and its metabolites in a series of heroin‐related deaths

The abuse of heroin (diamorphine) and heroin‐related deaths are increasing around the world. The interpretation of the toxicological results from suspected heroin‐related deaths is notoriously difficult, especially in cases where there may be limited samples. To help forensic practitioners with heroin interpretation, we determined the concentration of morphine (M), morphine‐3‐glucuronide (M3G), and morphine‐6‐glucuronide (M6G) in blood (femoral and cardiac), brain (thalamus), liver (deep right lobe), bone marrow (sternum), skeletal muscle (psoas), and vitreous humor in 44 heroin‐related deaths. The presence of 6‐monoacetylmorphine (6‐MAM) in any of the postmortem samples was used as confirmation of heroin use. Quantitation was carried out using a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method with solid‐phase extraction. We also determined the presence of papaverine, noscapine and codeine in the samples, substances often found in illicit heroin and that may help determine illicit heroin use. The results of this study show that vitreous is the best sample to detect 6‐MAM (100% of cases), and thus heroin use. The results of the M, M3G, and M6G quantitation in this study allow a degree of interpretation when samples are limited. However in some cases it may not be possible to determine heroin/morphine use as in four cases in muscle (three cases in bone marrow) no morphine, M3G, or M6G were detected, even though they were detected in other case samples. As always, postmortem cases of suspected morphine/heroin intoxication should be interpreted with care and with as much case knowledge as possible.     

Interaction of hesperetin glucuronide conjugates with human BCRP, MRP2 and MRP3 as detected in membrane vesicles of overexpressing baculovirus-infected Sf9 cells

The citrus flavonoid hesperetin (4'-methoxy-3',5,7-trihydroxyflavanone) is the aglycone of hesperidin, the major flavonoid present in sweet oranges. Hesperetin 7-O-glucuronide (H7G) and hesperetin 3'-O-glucuronide (H3'G) are the two most abundant metabolites of hesperetin in vivo. In this study, their interaction with specific ABC transporters, believed to play a role in the disposition and bioavailability of hesperetin, was studied using Sf9 membranes from cells overexpressing human BCRP (ABCG2), MRP2 (ABCC2) and MRP3 (ABCC3). Both H7G and H3'G were tested for their potential to activate and inhibit ATPase activity, and to inhibit vesicular transport by these transporters. Both H7G and H3'G demonstrated interaction with all tested ABC transporters, especially with BCRP and MRP3. An interesting difference between H7G and H3'G was seen with respect to the interaction with BCRP: H7G stimulated the ATPase activity of BCRP up to 76% of the maximal effect generated by the reference activator sulfasalazine, with an EC(50) of 0.45 μM, suggesting that H7G is a high affinity substrate of BCRP, whereas H3'G did not stimulate BCRP ATPase activity. Only moderate inhibition of BCRP ATPase activity at high H3'G concentrations was observed. This study provides information on the potential of hesperetin glucuronide conjugates to act as specific ABC transporter substrates or inhibitors and indicates that regio-specific glucuronidation could affect the disposition of hesperetin.     

Toxicological role of an acyl glucuronide metabolite in diclofenac‐induced acute liver injury in mice

The acyl glucuronide (AG) metabolites of carboxylic acid‐containing drugs are potentially chemically reactive and are suggested to be implicated in toxicity, including hepatotoxicity, nephrotoxicity and drug hypersensitivity reactions. However, it remains unknown whether AG formation is related to toxicity in vivo . In this study, we sought to determine whether AG is involved in the pathogenesis of liver injury using a mouse model of diclofenac (DIC)‐induced liver injury. Mice that were administered DIC alone exhibited significantly increased plasma alanine aminotransferase levels, whereas mice that were pretreated with the UDP‐glucuronosyltransferase inhibitor (−)‐borneol (BOR) exhibited suppressed alanine aminotransferase levels at 3 and 6 h after DIC administration although not significant at 12 h. The plasma DIC‐AG concentrations were significantly lower in BOR‐ and DIC‐treated mice than in mice treated with DIC alone. The mRNA expression levels of chemokine (C‐X‐C motif) ligand 1 (CXCL1), CXCL2 and the neutrophil marker CD11b were reduced in the livers of mice that had been pretreated with BOR compared to those that had been administered DIC alone, whereas mRNA expression of the macrophage marker F4/80 was not altered. An immunohistochemical analysis at 12 h samples revealed that the numbers of myeloperoxidase‐ and lymphocyte antigen 6 complex‐positive cells that infiltrated the liver were significantly reduced in BOR‐ and DIC‐treated mice compared to mice that were treated with DIC alone. These results indicate that DIC‐AG is partly involved in the pathogenesis of DIC‐induced acute liver injury in mice by activating innate immunity and neutrophils. Copyright © 2016 John Wiley & Sons, Ltd.     

Changes in PPARδ expression in a rat model of stress‐induced depression

Depression is a common mental disorder that has been linked to a decrease in the expression of serotonin and/or the serotonin transporter in the brain. Antidepressants that target the monoaminergic system are widely used in the clinical setting. Peroxisome proliferator‐activated receptor δ (PPAR δ) overexpression or activation is thought to improve depression‐like behaviours in rodents. The present study was designed to characterize the changes in PPARδ expression in the hippocampus in rats with stress‐induced depression. We used an unpredictable chronic mild stress (CMS) model in rats to study the role of PPARδ in the hippocampus. Behaviour was evaluated via a forced swim test (FST), a tail suspension test (TST), and a sucrose preference test (SPT). Then, the changes in PPARδ expression and other signals were determined using Western blots. We found that PPARδ expression in the hippocampus was markedly reduced in rats with depression. Moreover, the expression of the serotonin transporter was also significantly decreased. Treatment with a PPARδ agonist enhanced the expression of PPARδ and the serotonin transporter in the hippocampus of rats with stress‐induced depression. Additionally, treatment with a PPARδ agonist increased the expression of the serotonin transporter in cultured hippocampal (H19‐7) cells, and this action was ablated in the absence of PPARδ, which was attenuated with shRNA. Taken together, we found that PPARδ plays an important role in the regulation of serotonin transporter expression and that chronic stress may lower PPARδ expression in the brain via apoptosis and may attenuate serotonin transporter expression, thus inducing depression in rats.     

Synthesis of [2H3]‐dextromethorphan and its major urinary metabolites [2H3]‐dextrorphan and [2H3]‐dextrorphan‐β‐glucuronide

Starting from dextromethorphan, [²H₃]‐dextrorphan‐β‐glucuronide was synthesized in four steps with [²H₃]‐dextromethorphan and [²H₃]‐dextrorphan as intermediates with an overall yield of 11%. Copyright © 2002 John Wiley & Sons, Ltd.     

Interaction of morphine but not fentanyl with cerebral α2‐adrenoceptors in α2‐adrenoceptor knockout mice

Objectives α₂‐Adrenergic and μ‐opioid receptors belong to the rhodopsin family of G‐protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with α₂‐adrenoceptor‐subtypes in mice lacking one individual α₂‐adrenoceptor‐subtype (α₂‐adrenoceptor knockout). Methods Opioid interaction with α₂‐adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of α_2A‐, α_2B‐ or α_2C‐adrenoceptor deficient mice. Displacement of the radiolabelled α₂‐adrenoceptor agonist [¹²⁵I]paraiodoclonidine from α₂‐adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to α₂‐adrenoceptor subtypes in different brain regions was quantified. Key findings Morphine but not fentanyl or naloxone provoked dose‐dependent displacement of [¹²⁵I]paraiodoclonidine from all α₂‐adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of α_2A‐adrenoceptor knockout mice. Conclusions Our results indicated that morphine interacted with α₂‐adrenoceptors showing higher affinity for the α_2B and α_2C than for the α_2A subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to α₂‐adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.     

Effects of poloxamer 407‐induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats

Hepatic multidrug resistance‐associated protein 2 (Mrp2) is responsible for the majority of the biliary elimination of endogenous and exogenous substances, therefore it is important to evaluate possible functional changes in Mrp2 activity under conditions of hyperlipidemia (HL). Thus, the present study assessed the protein expression and transporting activity of hepatic Mrp2 based on the in vivo biliary excretion of phenolsulfonphthalein (PSP) as a model anionic substrate for Mrp2 in poloxamer 407‐induced hyperlipidemic rats (HL rats) and compared these values with those for control rats. The pharmacokinetics of mycophenolic acid (MPA) and mycophenolic acid‐7‐O‐glucuronide (MPAG) were evaluated after the intravenous (5 mg/kg) and oral (10 mg/kg) administration of MPA to control and HL rats. In HL rats, the protein expression of hepatic Mrp2 and its biliary transporting activity exhibited significant reductions (by 24.3% and 24.6%, respectively) in the absence of a change in bile flow rate. Unexpectedly, HL and control rats showed comparable biliary excretion rates of MPAG due to the counter effects of the reduced expression and activity of Mrp2 and a 484% increase in the free fraction of MPAG in HL rats. The estimated biliary clearance value of free MPAG in HL rats was considerably slower (by 77.1%) than that in control rats. Although significant pharmacokinetic changes in total MPA and MPAG levels were not observed in HL rats, there was a marked increase in free MPA and MPAG levels. Clinically relevant pharmacokinetic changes in subjects with HL that are related to MRP2 could not be ruled out. Copyright © 2016 John Wiley & Sons, Ltd.     

Effect of dimethylnitrosamine‐induced liver dysfunction on the pharmacokinetics of 5‐fluorouracil after administration of S‐1, an antitumour drug,to rats

Objectives The anti‐tumour agent S‐1 comprises tegafur (a prodrug of 5‐fluorouracil; 5‐FU), gimeracil (2‐chloro‐2,4‐dihydroxypyridine (CDHP); a competitive inhibitor of 5‐FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5‐FU after administration of S‐1 to rats was investigated. Methods S‐1 (5 mg/kg) was administered intravenously and orally to rats with DMN‐induced liver dysfunction. Plasma concentrations of S‐1 components and 5‐FU were measured by HPLC and LC/MS‐MS. Blood tests and in‐vitro enzymatic investigations were also conducted. Key findings DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5‐FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S‐1, the blood concentration‐time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half‐life of tegafur was significantly prolonged. The maximum plasma concentration (C_max) of 5‐FU was significantly reduced and the area under the blood concentration‐time curve (AUC) was reduced by 22%. Following oral administration, the C_max of tegafur, 5‐FU and CDHP were significantly decreased and half‐lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5‐FU (13.6% reduction). Conclusions The pharmacokinetic profiles of tegafur, 5‐FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5‐FU. However, hepatic dysfunction had less of an effect on the AUC of 5‐FU, which correlates with anti‐tumour effect, after the oral administration of S‐1.     

The effect of streptozotocin‐induced diabetes on cardiac β‐adrenoceptor subtypes in the rat

1 The present study investigates the effect of short‐term experimental diabetes of 14‐days duration on the β‐adrenoceptor subtypes of the rat heart. 2 β‐adrenoceptor‐mediated functional responses to submaximal doses of isoprenaline were enhanced in Langendorff‐perfused hearts from diabetic rats, manifested as greater changes in tension, heart rate and rates of tension development (+dT/dt) and decline (–dT/dt). 3 Radioligand binding data demonstrated that total cardiac β‐adrenoceptor density and affinity for [³H]‐dihydroalprenolol was unchanged by diabetes, although a decrease in β₁‐adrenoceptor density and increase in β₂‐adrenoceptor density was observed. 4 In conclusion, hearts from 14‐day streptozotocin‐induced diabetic rats demonstrate a number of alterations within the β‐adrenoceptor system. However, the enhanced β‐adrenoceptor‐mediated responses to isoprenaline were not caused by an overall increase in density of β‐adrenoceptors, but were accompanied by changes in the ratio of the β‐adrenoceptor subtypes.     

Lack of effect of ondansetron on the pharmacokinetics and analgesic effects of morphine and metabolites after single-dose morphine administration in healthy volunteers

AIMS: The purpose of this investigation was to study the influence of ondansetron on the single-dose pharmacokinetics and the analgesic effects elicited by morphine and the 3- and 6-glucuronide metabolites of morphine in healthy volunteers. METHODS: This was a randomized, double-blind, placebo-controlled, two-way crossover study in which six male and six female subjects were administered a single 10 mg intravenous dose of morphine sulphate, followed 30 min later by a single 16 mg intravenous dose of ondansetron hydrochloride or placebo. Serum and urine concentrations of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) samples were quantified over 48 h using high performance liquid chromatography with detection by mass spectrometry. Analgesia was assessed in the volunteers with a contact thermode device to provide a thermal pain stimulus. Four analgesic response variables were measured including thermal pain threshold, thermal pain tolerance, temporal summation of pain and mood state. RESULTS: The two treatments appeared to be equivalent based on the 90% confidence intervals (0.6, 1.67) of the least squares means ratio. All least squares means ratio confidence intervals for each parameter, for each analyte fell within the specified range, demonstrating a lack of an interaction. CONCLUSIONS: The results of this study suggest that administration of ondansetron (16 mg i.v.) does not alter the pharmacokinetics of morphine and its 3- or 6-glucuronide metabolites to a clinically significant extent, nor does it affect the overall analgesic response to morphine as measured by the contact thermode system.     

Pharmacokinetics of morphine in plasma and discrete areas of the rat brain

After intravenous administration of an analgesic dose of morphine into rat, the time course of morphine concentrations was followed in plasma, whole brain, and four discrete areas of the brain during 8 hr. These concentration curves indicated a three-exponential function which could be described by a mammillary system of three compartments. Maximal brain levels were obtained 15–20 min after injection, showing a fairly even distribution pattern of morphine. The plasma to whole brain ratio showed three-exponential characteristics, approaching a constant value of about 4.7–4.8 after 4 hr. By use of the SAAM-25 program, the experimental data from plasma and brain were simultaneously fitted to five separate sets of three-compartment models. Results obtained implied the uniqueness of the computed transfer constants of the three-compartment model.