Relationship between plasma concentrations of morphine and its metabolites and pain in cancer patients

Objective This study was undertaken to investigate the relationship between the plasma concentration of morphine, morphine-3-glucuronide and morphine-6-glucuronide and pain in cancer patients receiving oral morphine. Methods The trough value of plasma concentrations of morphine and its metabolites were measured by high performance liquid chromatography using an ultraviolet detector. Using this assay system, the plasma concentrations of morphine, morphine-3-glucuronide and morphine-6-glucuronide in 26 cancer pain patients were measured and compared with pain intensity. The pain intensity was assessed at the time of blood sampling using the visual analog scale. Results The trough value of morphine and morphine-6-glucuronide did not show a significant correlation with pain intensity by visual analog scale assessment, but morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine showed a significantly positive correlation (r = 0.528, P = 0.006 and r = 0.671, P < 0.001, respectively). By dividing the group according to low (≤ median value) or high (> median value) VAS scores a significant difference was found between the two groups in morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine (P = 0.045 and P = 0.007, respectively). Conclusion These results indicated that the level of morphine-3-glucuronide is related to the patient’s perception of morphine effect, and the plasma concentration of morphine-3-glucuronide and the ratio of morphine-3-glucuronide/morphine indicated potency to assess clinical effect.     

On-line clean-up system of plasma sample for simultaneous determination of morphine and its metabolites in cancer patients by high-performance liquid chromatography.

A convenient and sensitive analytical method for determination of plasma morphine and its metabolites in cancer patients was established using HPLC with a column-switching technique. Sample plasma which has been deproteinized with trichloroacetic acid is injected onto a precolumn, then the compounds of interest are preferentially introduced into the analytical column for separation and detection after washing out the unnecessary plasma components from the precolumn. Detection was simultaneously performed with coulometry for unchanged morphine and morphine-6-glucuronide and with UV analysis for morphine-3-glucuronide. Analytical recoveries were greater than 99% for these compounds, and the averaged coefficients of within-day or between-day variation did not exceed 5.5%. Detection limits were 0.2 ng/mL for morphine, 0.5 ng/mL for morphine-6-glucuronide, and 10 ng/mL for morphine-3-glucuronide. Correlation between the previously reported solid extraction method and this method was satisfactory in plasma samples after administration of morphine.     

Single-dose and steady-state kinetics of morphine and its metabolites in cancer patients — a comparison of two oral formulations

Summary The single-dose and steady state kinetics of morphine given as controlled-release tablets (30 mg every 12 h) and as a solution (15 mg every 6 h) have been compared in 11 cancer patients with chronic pain. The concentrations of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) were analyzed by HPLC.There were no significant differences between the tablets and solution in the mean steady state concentrations of morphine, M3G or M6G. The t_max was 3.3 h for the tablets compared to 1.1 h for the solution.After giving the controlled-release tablets every 12 h there was a significantly higher fluctuation index of the morphine concentrations than after the solution. Urinary recovery at steady state was comparable between the two preparations, with averages of 57% and 47%, respectively.Thus, no major differences were found in the pharmacokinetics of morphine and its glucuronidated metabolites after 30 mg morphine as controlled-release tablets every 12 h or 15 mg of morphine solution every 6 h, except for a significantly longer t_max and greater fluctuation in morphine concentrations after the controlled-release tablets.     

Relationship between morphine analgesia and cortical extracellular fluid levels of morphine and its metabolites in the rat: a microdialysis study.

1. The effect of morphine (10 mg kg-1, s.c.) on the analgesic response measured by the tail-flick method was determined in male Sprague-Dawley rats. The analgesic response to morphine was correlated with the levels of morphine and its metabolites collected by microdialysis from the cortical extracellular fluid (ECF). 2. The analgesic response to morphine lasted for 4 h. The concentration of morphine during a 4 h collection period was significantly higher than the metabolites concentration. The relative concentration of morphine and its metabolites during the 4 h period was 70 and 30% respectively. 3. The analgesic response during the first 2.25 h period accounted for more than 82% of the total analgesia as determined by the area under the time-response curve (AUC). The concentration of morphine and its metabolites during the same period were 78 and 22%, respectively, but they did not differ during the 2.25-4.0 h period (52 and 48%). 4. The half-life for morphine and its metabolites were similar, the maximal achievable concentration Cmax and AUC0-4 h were lower for metabolites but the time to reach maximum concentration was higher for morphine metabolites than for morphine. The ratio of the concentration of metabolites to the concentration of morphine in the cortical ECF increased with time whereas the analgesic response to morphine decreased with time. 5. At several time points following morphine injection even though the levels of morphine were the same, the concentration of metabolites (mainly M3G) differed and thus the ratio [metabolite/morphine]. A plot of [metabolite]/[morphine] vs. analgesia gave a high correlation coefficient. Since M3G has been shown to be antianalgesic and is the only metabolite of morphine in the rat, it is concluded that the levels of this metabolite may regulate the analgesic effect of morphine in the rat.     

Doxepin and its metabolites in plasma and cerebrospinal fluid in depressed patients

Little information exists on the concentrations of antidepressants and their metabolites in CSF. We measured plasma and CSF levels of trans-doxepin (trans-DOX) and DOX metabolites in 12 depressed patients treated with DOX (250 mg/day) for 6 days. Spinal taps and blood samples were taken on day 7, 10 h after drug administration. Trans-DOX, cis-desmethyldoxepin (cis-DM-DOX), trans-desmethyldoxepin (trans-DM-DOX) and di-desmethyldoxepin (DDM-DOX) were analyzed in CSF and plasma samples by HPLC with column-switching. Although DOX was given as a mixture of 85% trans-DOX and 15% of the pharmacologically more active cis-DOX, we found similar amounts of cis-DM-DOX and trans-DM-DOX in plasma (59.8 ± 45.1 versus 72.0 ± 60.0 ng/ml; NS), suggesting that isomerization of DOX had taken place. Trans-DOX and DOX metabolites could be detected in CSF of most patients. Relatively low CSF concentrations of the active metabolite cis-DM-DOX were measured. Clinical efficacy, as assessed by HAMD scores, was not significantly related to plasma or CSF concentrations of trans-DOX or its metabolites. Trans-DOX and DOX metabolites were distributed differently between plasma and CSF. It is concluded that isomerization of DOX is not only relevant for neuronal uptake inhibition, but also for the transport of the metabolites. Received: 13 May 1996/Final version: 16 December 1996     

Gender differences in plasma clozapine levels and its metabolites in schizophrenic patients

Forty refractory schizophrenic patients (21 females and 19 males) participated in a fixed-dose study with clozapine. After a 6-week trial of haloperidol and a 1-week washout time period, non-responding patients were placed on clozapine and the dosage titrated up to 400 mg/day for the next 5 weeks. Plasma clozapine levels and its two metabolites desmethylclozapine (DCLOZ) and clozapine N-oxide (CNO) were measured at weeks 2, 4 and 6. Blood samples were obtained 10–12 h post-evening dose and prior to the morning dose. Clozapine and its metabolites were assayed by HPLC with UV detection. Patients were assessed for clinical response with the Brief Psychiatric Rating Scale (BPRS) at baseline and at weeks 2, 4 and 6. BPRS scores were also divided into positive (+) and negative (−) symptoms subscales. Plasma clozapine and DCLOZ levels were significantly lower in males. Plasma CNO levels were slightly lower in males but it was not statistically significant. Decreased total BPRS, (+) and (−) symptoms subscale scores occurred during the study for both gender groups. A greater magnitude of change for the (−) symptom subscale score was observed in the male group. Gender was not a significant factor in the incidence or severity of side-effects. © 1997 John Wiley & Sons, Ltd.     

Interindividual variation in the extent and rate of phenytoin accumulation

Steady-state serum phenytoin concentration (Css) is known to increase nonlinearly with dose, but it is less well recognized that the rate of phenytoin accumulation is also dose dependent. This stimulation study estimated the extent and rate of phenytoin accumulation in a sample of 95 adult subjects, with known values of Vmax and Km, pooled from the literature. Simulations were done using a Michaelis-Menten model and phenytoin sodium doses of 200, 300, and 400 mg/day. The distributions of Css and the time required to reach 90% of steady state (T90) became increasingly positively skewed as dose was increased. The T90 and Css were positively correlated (r greater than or equal to 0.8880, p less than 0.00001) and subjects reached 90% or more of Css more slowly as the initial phenytoin dose was increased. At an initial dose of 300 mg/day of phenytoin sodium, mean Css was 11.0 +/- 9.10 micrograms/ml (median, 7.62 micrograms/ml), and mean T90 was 12.2 +/- 15.4 days (median, 5.98 days). Only 25.3% of the subjects would be expected to achieve therapeutic serum concentrations (10-20 micrograms/ml) on this dose, and 88.4% would reach 0.9 Css within 30 days. Phenytoin dosage must be individualized to achieve concentrations of 10-20 micrograms/ml. Multiple serum phenytoin determinations during the first 30 days or more are required to determine that steady state has been reached, but these need not be done more often than once a week.     

Clinical pharmacokinetics of capecitabine and its metabolites in colorectal cancer patients

BackgroundCapecitabine is one of the fluoropyrimidine anticancer agents which is extensively used in the management of colorectal cancer. We have noticed a discrepancy between the doses we are using in our patients and the recommended dosing regimen. Thus, this study aims to assess the pharmacokinetic parameters of capecitabine and its metabolites in colorectal cancer patients and report some clinical outcomes.MethodsThis study is a prospective observational pharmacokinetic study. It was conducted at the Oncology Center at King Saud University Medical City. The study included adult patients who received capecitabine for any stage of colorectal cancer. Blood samples were collected following the oral administration of capecitabine. Capecitabine and its metabolites concentration in plasma were determined using HPLC and pharmacokinetic parameters were estimated using PKanalix software.ResultsThe study included 30 colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1. 60 % of the patients were in stage IV. The average total daily dose was 1265 ± 350 mg/m²/day. C_max for capecitabine was 5.2 ± 1.3 μg/ mL and T_max was 1 ± 0.25 h. AUC_last for capecitabine was 28 ± 10 μg.h/ mL. Vd_obs and Cl_obs for capecitabine were 186 ± 28 L and 775 ± 213 mL/min, respectively. Calculated half-life (t_1/2) was 2.7 h. Half of our patients showed partial tumor response and 20% showed stable disease. Only two patients had to discontinue the treatment because of the toxicity.ConclusionDespite using lower doses, capecitabine and its metabolites parameters were found to be similar to previous studies except for the longer half-life found in our patients. In addition, lower doses of capecitabine showed acceptable response rate which might indicate that higher doses are not always necessary to achieve desired therapeutic effect.     

Relationship between plasma morphine concentrations and pharmacologic effects in postoperative patients using patient-controlled analgesia

In postoperative patients using patient-controlled analgesia (PCA) to administer i.v. doses of morphine sulfate, respiratory rates and subjective rankings of pain, sedation, and liking for the drug were correlated with plasma morphine concentrations. In 12 patients selected before surgery, the initial morphine sulfate dose of 0.6 mg/sq m was increased or decreased as needed. Every two hours, cumulative morphine sulfate dose, respiratory rate, and sedation were recorded by the nurse, along with the patient's evaluation of pain and liking for the drug. Plasma was collected in the morning and evening during PCA therapy for morphine analysis. Data were analyzed by analysis of covariance. Dosing rates and rankings of pain, sedation, and liking decreased as a function of time postoperatively, but respiratory rates did not. Sedation and respiratory rates were independent of morphine concentration. Liking of the drug increased directly with plasma morphine concentration but decreased with time. A high level of pain was directly related to morphine use. For all significant relationships, there was high interpatient variability, with the exception of changes in pain rankings induced by morphine. Patients defined a minimum effective plasma morphine concentration of 20-40 ng/mL. The maximum plasma morphine concentration achieved by self-administration was 82 ng/mL. These postoperative patients used patient-controlled analgesia to deliver morphine sulfate i.v. for pain relief, not for euphoria, and did not exhibit sedation or respiratory depression. Morphine was consistently effective at plasma concentrations of 40 ng/mL or greater.     

Radioassay of chlorpromazine and its metabolites in plasma

Conditions have been established for the quantitative formation of radiolabeled derivatives of chlorpromazine, chlorpromazine sulfoxide and their demethylated analogs in plasma extracts.Tritiated N-acetyl derivatives are formed from the demethylated compounds and C¹⁴-quaternary amines from the tertiary amines by acetylation and methylation, respectively. These reactions are quantitative over a wide range of concentrations.The reactions may be performed sequentially when chloropromazine and its Nor derivatives (or chlorpromazine sulfoxide and its Nor derivatives) exist in a single extract. Herein, the mixture is first acetylated and subsequently methylated. The labeled derivatives are quantitatively separated and recovered by selective solvent partition.An extraction procedure has been suggested by which chlorpromazine and its Nors may be separated from chlorpromazine sulfoxide and its Nor derivatives so that each fraction may be subjected to the sequential acetylation and methylation reactions. Recoveries of g quantities of standards from plasma are less than quantitative, probably because of losses due to glass adsorption and protein binding, but may be corrected with appropriate internal standards. As low as 15–20 ng/ml of each compound are measurable in a 3 ml plasma aliquot.The method has been applied to a limited number in vivo experiments in dogs and in humans.This investigation was supported under a Public Health Service contract (No. PH-43-65-68) to the New England Nuclear Corporation, Biomedical Assay Laboratories, Boston, Massachusetts.New England Nuclear Corporation, Biomedical Assay Laboratories.     

The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients.

1. The relationships between renal creatinine clearance and the renal clearances of morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) were studied in fifteen intensive-care patients who were receiving morphine sulphate by constant intravenous infusion and who had diverse renal function. 2. An arterial blood sample was collected before and after a 4-5 h urine collection. Plasma and urine concentrations of morphine, M3G and M6G were measured by h.p.l.c. Plasma binding of all three compounds in drug-free plasma from healthy volunteers was determined by ultrafiltration. Measured renal creatinine clearance (CLCr,meas) was calculated from plasma and urinary creatinine concentrations (from h.p.l.c.). Also, creatinine clearance was predicted (CLCr,pred) from routine laboratory determination of plasma creatinine (Jaffe method). 3. There were significant linear relationships (P less than 0.001) between CLCr,meas and the renal clearances of morphine, M3G and M6G. The unbound renal clearance of morphine exceeded CLCr,meas (P less than 0.002) while the unbound renal clearances of M3G and M6G did not differ from CLCr,meas (P greater than 0.5). 4. In ten of the patients who received a constant infusion of morphine for at least 6 h, the dose-normalised plasma concentrations of M3G and M6G increased with decreasing CLCr,pred. Significant (P less than 0.001) relationships were observed between the reciprocal of CLCr,pred and the dose-normalised plasma concentrations of M3G and M6G. 5. The results indicate the importance of renal function in determining the renal clearances and plasma concentrations of M3G and M6G during intravenous infusion with morphine in intensive-care patients.     

环孢素与其3种代谢物的浓度相关性和生物转化的分析

目的:测定患者服用环孢素后全血中环孢素及其代谢物浓度,分析环孢素与其3种代谢物的浓度之间的关系,研究环孢素体内代谢规律.方法:30例肾移植患者口服环孢素后12h采用液相色谱-质谱联用仪测定环孢素与其3种代谢物的全血浓度,采用线性回归法计算环孢素与其3种代谢物的浓度相关系数,评价相关性.结果:环孢素与去甲环孢素、羟化环孢素及二羟化环孢素的相关性逐步递增,相关系数分别为0.515 1,0.788 7,0.808 4.羟化环孢素浓度与二羟化环孢素浓度具有较强的相关性,相关系数为0.865 1.结论:测定环孢素及其3种代谢产物不仅是延长移植器官在体生存期,避免肝肾性综合体征反应的-种有效的方法,而且对于个体化用药具有重要意义.     

Interindividual variation in bromperidol metabolism and relationship to therapeutic effects

Plasma concentrations of bromperidol (BRP) and reduced bromperidol (RBRP) were determined in 31 patients with schizophrenia who were administered BRP for their psychiatric symptoms. Activities of carbonyl reductase in red blood cells were assayed using BRP as a substrate. Plasma concentrations of BRP and RBRP ranged from 2.2 to 23.5 ng/mL and from 0.2 to 8.2 ng/mL, respectively. RBRP-to-BRP ratios in plasma ranged from 0.01 to 0.94 (mean +/- SD: 0.31 +/- 0.20), values notably lower than the previously reported values of reduced haloperidol to haloperidol (HAL) in the plasma from patients on HAL. The activity of BRP reductase in red blood cells was determined as 6.8-12.3 pmol/hr/10(6) red blood cells, which was at approximately the same level as that of HAL reductase. Patients with positive responses to BRP treatment were evaluated using the Brief Psychiatric Rating Scale. We found that the number of patients who had a positive response to BRP did not increase after BRP plasma levels had reached the level of 12 ng/mL. This finding suggests that a therapeutic plateau in BRP pharmacotherapy of schizophrenia occurs, and there is no advantage to raising the dose once this plateau is reached.     

Effect of plasma from patients containing bupropion and its metabolites on the uptake of norepinephrine

The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the presence of buffer and plasma from patients containing bupropion and its metabolites. Even though bupropion and its metabolite (compound II) were equipotent in inhibiting the uptake of NE in buffer, compound II was twice as active as bupropion in the presence of human plasma. When the inhibition of uptake of NE in the presence of plasma, obtained from patients on bupropion on steady-state, was correlated with levels of bupropion and its metabolites (II, III, IV) a highly significant correlation was seen in the presence of compound II. Since this compound accumulated in plasma from patients 20-100 times that of the parent compound, the mode of action of bupropion may in part be due to the effect of this compound on the uptake of NE.     

Plasma concentrations of 5-fluorouracil and its metabolites in colon cancer patients.

5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd and, in fact, in our patients these metabolites were detected only in few samples, but most of them at day 5. In conclusion, our study confirms the relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5-FUH2, to better understand the metabolism and to improve the therapeutic efficacy.     

Interindividual variabilities in haloperidol interconversion and the reduced haloperidol/haloperidol ratio.

Metabolism of haloperidol in humans includes N-dealkylation to inactive metabolites and reduction to reduced haloperidol; reduced haloperidol is also oxidized back to haloperidol. A single 0.5 mg/kg (0.00133 mmol/kg) oral dose of haloperidol and reduced haloperidol was administered to seven Chinese schizophrenics in a randomized crossover manner separated by a 2-week interval. The clearance values for the different metabolic pathways of haloperidol and reduced haloperidol were determined. There were differences up to 10-fold in both oxidation and reduction capacities. There were also interindividual variabilities in the elimination of reduced haloperidol (0.37 +/- 0.20 L/hr/kg) and the N-dealkylation pathway (0.74 +/- 0.36 L/hr/kg). Four weeks after the single-dose study, the same patients also received haloperidol (10 mg) twice daily for 4 weeks. The reduced haloperidol to haloperidol concentration ratio (0.40 +/- 0.16) after the 4-week therapy is related to individual variabilities in the interconversion process and the N-dealkylation pathway of haloperidol.     

Interindividual variation in the capacity-limited renal glucuronidation of probenecid by humans

A dose of 1,000 mg probenecid was administered orally to 14 human volunteers in order to quantify the maximal rate of formation and excretion of probenecid acyl glucuronide in the urine. Probenecid showed dose-dependent pharmacokinetics. Plasma protein binding of probenecid was high, being somewhat higher in males (90.7±1.4%) than in females (87.9±1.4%; p=0.0019). It was shown that probenecid is metabolized by cytochrome P-450 into at least two phase I metabolites. Each of the metabolites accounted for less than 12% of the dose administered; the main metabolite probenecid acyl glucuronide, representing 42.9±13.2% of the dose, was only present in urine and not in plasma. The renal excretion rate-time profile of probenecid acyl glucuronide showed a plateau value in the presence of an acidic urine pH. This plateau value was maintained for about 10 h at the dose of 1,000 mg. The height of the plateau value depended on the individual and varied between 250 and 800g/min (15–50 mg/h). It was inferred that probenecid acyl glucuronide is formed in the kidney during blood-to-lumen passage through the tubular cells. We conclude that the plateau value in the renal excretion rate of probenecid glucuronide reflects itsV _max of formation.