Showing papers in "Therapeutic Drug Monitoring in 1994"
TL;DR: It is concluded that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels.
Abstract: Therapeutic drug monitoring data for clozapine were used to study interactions with other drugs. The distribution of the ratio concentration/dose (C/D) of clozapine was compared in four matched groups--patients simultaneously treated with benzodiazepines, patients on drugs that inhibit the cytochrome P450 enzyme CYP2D6, patients taking carbamazepine, and those not taking any of these drugs. No difference was seen among the monotherapy, CYP2D6, and benzodiazepine groups. Patients on carbamazepine had a mean 50% lower C/D than the monotherapy group (p < 0.001), indicating that carbamazepine is an inducer of the metabolism of clozapine. The C/D was inversely correlated to the daily dose of carbamazepine. Intraindividual comparisons in eight patients, with analyses both on and off carbamazepine, confirmed a substantial decrease of the clozapine concentration when carbamazepine was introduced. Four patients treated with clozapine were concomitantly given the antidepressant fluvoxamine. Three of them exhibited a much higher C/D ratio when on fluvoxamine compared with the monotherapy group. Two had their clozapine levels analyzed when on and off fluvoxamine. The dose-normalized clozapine concentration increased by a factor of 5-10 when fluvoxamine was added. We conclude that carbamazepine causes decreased clozapine plasma levels, while fluvoxamine increases the levels. The pathways are not known with certainty, but CYP1A2 may be of major importance for the metabolism of clozapine, since fluvoxamine is a potent inhibitor of this enzyme. A recent panel study suggests that determination of CYP1A2 activity with the caffeine test may be very useful for the dosing of clozapine. The induction of clozapine metabolism by carbamazepine might be partly mediated by CYP3A4.
264 citations
TL;DR: Regression analysis indicated that V was more predictable in women than in men and that vancomycin distributed into excess body weight (EBW) to a greater extent in women, and dosing of vancomYcin may be improved by adjusting initial estimates of V for patient age, gender, and obesity.
Abstract: SummaryThe effects of age, gender, and body weight on the pharmacokinetics of vancomycin were examined using data collected as part of routine therapeutic drug monitoring in patients. One thousand eighty-five sets of steady-state peak and trough serum concentrations obtained from 704 different patie
134 citations
TL;DR: The proportion of heterozygous compared to homozygous EMs is higher in Orientals than in Caucasians, which might explain the higher clearance of omeprazole in Caucasian EMs compared to the clearance in Chinese and Korean EMs of S-mephenytoin.
Abstract: Two independent studies showed that the 5-hydroxylation, but not the sulfoxidation, of omeprazole is more rapid in extensive metabolizers (EMs) than in poor metabolizers (PMs) of S-mephenytoin. In Caucasian, Chinese, and Korean PMs, the mean oral clearances were similar and not significantly different (85, 73, and 59 ml h-1 kg-1, respectively). However, the geometric mean clearance in Caucasian EMs (950 ml h-1 kg-1) was higher than in both Chinese EMs (426 ml h-1 kg-1, p < 0.05) and Korean EMs (446 ml h-1 kg-1, p < 0.01). The incidence of PMs of S-mephenytoin is higher in Chinese (14.6%) and Koreans (12.6%) than in Swedish Caucasians (3.3%). Therefore, the proportion of heterozygous compared to homozygous EMs is higher in Orientals than in Caucasians. This might explain the higher clearance of omeprazole in Caucasian EMs compared to the clearance of omeprazole in Chinese and Korean EMs of S-mephenytoin.
105 citations
TL;DR: Five cases where fluvoxamine (FLVX) was added to maintenance treatment with methadone (MTD) in addict patients with affective disorders are reported, with clinical manifestations of opiate withdrawal after stopping FLVX therapy in one case.
Abstract: We report five cases where fluvoxamine (FLVX) was added to maintenance treatment with methadone (MTD) in addict patients with affective disorders In view of the implication of FLVX in several metabolic drug interactions, MTD plasma levels were measured before and after treatment with FLVX A slight increase (approximately 20% of the MTD plasma level/dose ratio) occurred in two cases In the remaining three patients, the interaction was more pronounced (40-100% increase of the MTD plasma level/dose ratio), with clinical manifestations of opiate withdrawal after stopping FLVX therapy in one case Caution is needed when starting or stopping treatment with FLVX in patients receiving maintenance treatment with methadone
82 citations
TL;DR: A quantitation limit of 10 ng/ml for plasma was adequate for their estimation over a period of three half-lives, following administration of a pharmacologic dose in man, and the limit of 0.1 μ/ml, for urine, can monitor excretion of as little as 0.5% of the dose.
Abstract: SummaryA rapid, accurate, and sensitive high-performance liquid chromatographic (HPLC) method for simultaneous determination of venlafaxine (V) and O-desmethylvenlafaxine (ODV) in plasma and urine has been developed. V and ODV are extracted from plasma using a liquid-liquid extraction procedure, chr
80 citations
TL;DR: The steady-state pharmacokinetics of cyclosporine from the microemulsion formulation exhibit greater within-day consistency compared to the commercial formulation in stable renal allograft recipients.
Abstract: A new microemulsion formulation of cyclosporine (Sandimmune Neoral) was compared to the commercially available formulation (Sandimmune) in 11 stable renal transplant patients with regard to the consistency in cyclosporine pharmacokinetics between a daytime fasting, and a nighttime nonfasting administration. Daily cyclosporine doses were individualized and administered in equal, divided doses every 12 h as soft gelatin capsules; doses were kept constant throughout the study. Serial blood samples were obtained over a 24-h period (two consecutive dosing intervals) at steady-state for each formulation, and cyclosporine concentrations were determined in whole blood by a specific radioimmunoassay method. Within-formulation consistency in pharmacokinetic parameters between the daytime and nighttime administrations was assessed in terms of bioequivalence criteria. Following the mg-to-mg conversion from the commercial to the microemulsion formulation, area under the curve (AUC) was increased on average by 30% due to absorption-related pharmacokinetic differences, while trough concentrations remained in the therapeutic range. Within each formulation, AUC was bioequivalent when comparing the daytime fasting to the nighttime nonfasting administration. For the commercial formulation, however, there was considerable variation in absorption rate, dampening of peak-trough fluctuation, and elevation of trough concentration following the nighttime nonfasting dose. By contrast, the microemulsion exhibited a more stable concentration-time profile over the two dosing intervals, with bioequivalence in peak-trough fluctuation and trough concentrations. Hence, the steady-state pharmacokinetics of cyclosporine from the microemulsion formulation exhibit greater within-day consistency compared to the commercial formulation in stable renal allograft recipients.
73 citations
TL;DR: Saliva sampling appears to be a less expensive and more acceptable procedure for children requiring TDM, and could be individualized according to patient and parent preferences.
Abstract: The objective of this study was to conduct an assessment of patient and parental preferences and an economic analysis of hospital costs in sampling blood and saliva for therapeutic drug monitoring (TDM). Costs and preferences were evaluated in the course of a study, which compared anticonvulsant concentrations in blood routinely drawn for therapeutic monitoring and in saliva in infants and children attending a pediatric neurology clinic. Parents of 84.8% of children, and half of the children, indicated a preference for saliva sampling over venous blood drawing. Children who had been on medications that required therapeutic monitoring for or = 2 years. Computation, based upon a basic assumption that a registered nurse obtained blood and a medical technician or a registered nurse assistant sampled saliva, indicated that for every 1,000 cases of changing from blood to saliva sampling, total cost savings would amount to $1,930 for cooperative children and $1,660 for infants and uncooperative children. This saving is equivalent to approximately 100 h of a registered nurse's initial salary. The important contributions to the differential cost were derived from the requirements for more highly trained individuals to take the blood sample and from the doubling time required for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
59 citations
TL;DR: An original, sensitive, and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of morphine and its two major metabolites, morphine-3-glucuronide (M3G) and morphine-6- glucuronides (M6G), in human plasma and cerebrospinal fluid (CSF) and in rat plasma, using hydromorphone as the internal standard.
Abstract: An original, sensitive, and specific high-performance liquid chromatographic (HPLC) assay was developed for the quantitation of morphine and its two major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), in human plasma and cerebrospinal fluid (CSF) and in rat plasma, using hydromorphone as the internal standard. Solid-phase extraction was used to separate morphine and its glucuronide metabolites from plasma constituents. Extraction efficiencies of morphine, M3G, and M6G from human plasma samples (0.5 ml) were 84, 87, and 88%, respectively. Extraction efficiencies of morphine, M3G, and M6G did not differ significantly (p > 0.05) between human plasma and CSF or rat plasma. Morphine, M3G, M6G, and hydromorphone were separated on a 10 mu C-8 Resolve radially compressed cartridge using a mobile phase comprising methanol:acetonitrile:phosphate buffer, (0.0125M pH 7.5; 10: 10:80), in which 11 mg/L of cetyltrimethylammonium bromide (cetrimide) was dissolved. Quantitation was achieved using a single electrochemical detector at ambient temperature (23-degrees-C). Standard curves were linear over the ranges 0.020-2.190, 0.027-2.709, and 0.027-0.542 muM for morphine, M3G, and M6G, respectively. Lower limits of detection for morphine, M3G, and M6G in human plasma and CSF samples (0.5 ml) were 0.020, 0.027, and 0.027 muM, respectively. Corresponding lower limits of detection in rat plasma (0.1 ml) were 0.102, 0.135, and 0.135 muM, respectively. Intraassay precision for low and high concentrations of morphine, M3G, and M6G were <23 and <8% respectively. Similarly, interassay accuracy for low and medium concentrations of morphine, M3G, and M6G were <17% and were <9% for high concentrations.
59 citations
TL;DR: Comparisons of the ratio CID in subjects with analyses performed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D6) inhibit the metabolism of NT and that carbamazepine induces the metabolismof both AT and NT.
Abstract: Therapeutic drug monitoring data for amitriptyline (AT) and nortriptyline (NT) collected during 10 years (total of 4,278 analyses in 2,937 patients) were evaluated to study how other drugs affect the kinetics at steady state. The distribution of the ratio concentration/daily dose (C/D) in patients treated with the antidepressant only was compared with that in patients on different concomitant drugs. Patients on phenothiazines or dextropropoxyphene had a significantly higher mean C/D of NT than controls, both when AT and when NT had been given. The highest values were seen with levomepromazine and thioridazine. On the contrary, the mean C/D of both AT and NT in patients on carbamazepine was about 50% lower than in those treated with the antidepressant only. Benzodiazepines did not affect the steady-state kinetics of AT or NT. Intraindividual comparisons of the ratio C/D in subjects with analyses performed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D6) inhibit the metabolism of NT and that carbamazepine induces the metabolism of both AT and NT. Modeling of the dose dependency of the NT interactions with levomepromazine, perphenazine, and thioridazine revealed that the ratio C/D was most affected at low doses of the antidepressant and at high doses of the phenothiazine. The distribution of the doses given was the same in patients on monotherapy as in patients with interacting drugs, which means that many patients treated with phenothiazines had concentrations above the therapeutic range and that most patients treated with carbamazepine had subtherapeutic levels. The present study shows that therapeutic drug monitoring may serve as a valuable tool to discover and quantify drug interactions.
57 citations
TL;DR: Serum levels of meprobamate recorded (15–25 μmol/L) indicate that meproBamate might contribute to the effect(s) of carisoprodol, and this subject was found to be a poor metabolizer of mephenytoin.
Abstract: The elimination of the muscle relaxant drug, carisoprodol, was examined in 10 healthy volunteers after an oral dose of 700 mg. In nine subjects, carisoprodol was rapidly eliminated, with a mean half-life of 99 +/- 46 min, and extensively converted to meprobamate. Within 2.5 h after carisoprodol intake, meprobamate serum concentrations exceeded those of carisoprodol. Serum levels of meprobamate recorded (15-25 mumol/L) indicate that meprobamate might contribute to the effect(s) of carisoprodol. One subject eliminated carisoprodol with an overall half-life of 376 min, and only small amounts of meprobamate were recorded. This subject was found to be a poor metabolizer of mephenytoin. In spiked human sera, protein binding of carisoprodol was in the range of 41-67%, whereas meprobamate was bound to a lesser extent, 14-24%.
56 citations
TL;DR: It is concluded that while undergoing ECMO, neonates have a higher volume of distribution for gentamicin, a lower clearance, and a much longer half-life.
Abstract: Prior authors had hypothesized (but not clearly found) an increased apparent volume of distribution (Vd) for gentamicin in neonates undergoing extracorporeal membrane oxygenation (ECMO). We chose to study the question in our own clinical setting. To develop population pharmacokinetic models of the drug, we used the nonparametric expectation and maximization population modeling method and data from 11 neonates who received gentamicin on ECMO, including 6 infants who received gentamicin both on and off ECMO for severe respiratory failure. We found an increased Vd for gentamicin on ECMO and attributed much of the difference from prior investigations to our use of an explicitly determined laboratory assay error pattern for the measured serum concentrations rather than using constant weighting of the serum level data points. For six infants, while on ECMO their median Vd was 0.748 L/kg compared with a median Vd of 0.471 L/kg after ECMO was discontinued. The median clearance of gentamicin in the six infants while undergoing ECMO was 0.239 L/h compared with 0.350 L/h after ECMO was discontinued. The median half-time (T1/2) was 9.24 h while on ECMO compared with 3.87 h when off ECMO. We conclude that while undergoing ECMO, neonates have a higher volume of distribution for gentamicin, a lower clearance, and a much longer half-life.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Plasma, rather than whole blood, would be the most suitable medium for analysis because of the higher concentrations of the drug found in this fraction of MPA, as well as the lack of temperature or concentration dependence.
Abstract: RS-61443 (RS) a morpholinoethyl ester of mycophenolic acid (MPA), can be considered a prodrug, as immunosuppressive activity is expressed only after hydrolysis to MPA upon absorption. Little is known about the blood distribution of MPA; such information would have an impact on the medium used for analysis of the drug in clinical trials. This was investigated by spiking whole blood having an initial temperature of either 4 degrees or 22 degrees C with increasing amounts of MPA ranging from 100 to 10,000 micrograms/L. These drug concentrations span the range seen when immunosuppressive doses of the RS are administered. This was followed by incubation of the blood at 37 degrees C for 0-120 min prior to separation of the cells. The drug concentration was measured in the plasma and whole blood fractions by high-performance liquid chromatography. MPA was almost exclusively found in the plasma fraction and did not exhibit any temperature or concentration dependence. The free or unbound fraction of MPA over the same concentration range was determined by ultracentrifugation and demonstrated a concentration dependence ranging from 7.2 to 16.5% of total drug for a concentration range spanning 500-10,000 micrograms/L. The drug was found to be primarily associated with the non-albumin proteins in the plasma. Less than 10% of the drug was found to be bound to lipoproteins. The data suggest that from an analytical standpoint, plasma, rather than whole blood, would be the most suitable medium for analysis because of the higher concentrations of the drug found in this fraction.
TL;DR: Elevated free phenytoin fraction was found in those with hypoalbuminemia and hepatic and renal impairments, and these patients should be measured routinely.
Abstract: Phenytoin binding to serum proteins and factors influencing protein binding were investigated in 38 critically ill trauma patients In 24% of these patients, the free fraction of phenytoin was less-than-or-equal-to 10%, whereas in 76%, the free phenytoin fraction was increased >10%-up to 24% Nonantiepileptic comedication, sex, or age had no influence on phenytoin binding in any of the 38 patients Elevated free phenytoin fraction was found in those with hypoalbuminemia and hepatic and renal impairments In these patients, the free phenytoin fraction should be measured routinely
TL;DR: With the pharmacokinetic population data from the single-dose study, the CTZ steady-state concentrations during CI could be predicted and may serve as a model in the development of CTZ continuous-infusion dosage regimens in CF home treatment.
Abstract: Acute exacerbations of Pseudomonas aeruginosa lung infections were treated with ceftazidime (CTZ) by continuous infusion (CI) in eight adult cystic fibrosis (CF) patients. CTZ pharmacokinetics were studied after a single dose and during CI (100 mg/kg/24 h) with a CADD-PLUS infusion pump at home for 3 weeks. Individual CTZ pharmacokinetic parameters after single-dose administration were a half-life (t1/2 beta) of 1.90 +/- 0.85 h (mean +/- SD), a volume of distribution (Vs) of 0.28 +/- 0.08 L/kg, and a total body clearance (CL) of 0.152 +/- 0.014 L/h/kg. CL during CI was 0.147 +/- 0.019 L/h/kg, equal to the CL after a single dose. CTZ clearance at the start and at the end of the treatment did not differ. The mean fraction of the dose recovered from the urine was 92.6% (range 85.6-98.5%). Renal clearance was 0.147 +/- 0.015 L/h/kg and was not influenced by the pulmonary exacerbation. The early-morning serum concentrations were significantly higher than the afternoon levels (p < 0.02). The mean CTZ serum concentration during CI was 28.7 +/- 5.0 mg/L. Clinical condition and quality of life improved significantly during and after treatment. With the pharmacokinetic population data from the single-dose study, the CTZ steady-state concentrations during CI could be predicted [precision (root mean squared prediction error) 3.1 mg/L; bias (mean prediction error) 0.4 mg/L]. This method may serve as a model in the development of CTZ continuous-infusion dosage regimens in CF home treatment.
TL;DR: An isocratic liquid-chromatographic method employing one extraction step has been developed for the quantitation of five drugs and three metabolites in human plasma using 0.100-ml aliquots of human plasma and two internal standards.
Abstract: An isocratic liquid-chromatographic method employing one extraction step has been developed for the quantitation of five drugs and three metabolites in human plasma. The method uses 0.100-ml aliquots of human plasma and two internal standards. Chromatographic conditions include a 4.6 mm x 150 mm Spherisorb ODS2, 3 microns a high-performance liquid chromatography, (HPLC) column, a phosphate buffer-acetonitrile-methanol (700:160:140) mobile phase, and ultraviolet (UV) absorbance detection at 210 nm. Analytes and linear quantitation ranges (microgram/ml) were felbamate (FBM) 0.391-200; primidone (PRIM), 0.098-100; phenobarbital (PHENO), 0.195-100; carbamazepine (CBZ), 0.195-100; phenytoin (PHT), 0.195-200. For CBZ-transdiol (CBZ-TR) CBZ-epoxide (CBZ-EP), and the PHT metabolite, 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH), the range was 0.049-25.0 micrograms/ml. Ethosuximide, methsuximide, 2-methyl-2-phenyl-succinimide (methsuximide metabolite), 2-ethyl-2-phenyl malonamide (PRIM metabolite, 5-ethyl-5-(4-hydroxyphenyl)-barbituric acid (PHENO metabolite), and mephenytoin do not interfere with quantitation of the above compounds.
TL;DR: Concomitant use of caffeine and carbamazepine may interfere with MEGX and bupivacaine determination, respectively, and in patients receiving one of these two drugs (or ingesting foods and beverages containing caffeine), the described method is not recommended.
Abstract: SummaryA gas-liquid chromatographic method for the simultaneous measurement in serum of bupivacaine, lidocaine, and their main metabolites, 2,6-pipecolylxylidide (PPX) and monoethylglycine xylidide (MEGX), respectively, is described. The procedure involves a one-step extraction and injection of the
TL;DR: This work reports on the first method that allows determination of both cocaine and nicotine as well as their metabolites in the same hair samples, which is an excellent tool in correlating in utero exposure and outcome.
Abstract: Maternal exposure to drugs and chemicals is increasingly being recognized as adversely affecting the developing fetus. To date, a very large number of fetuses have been exposed in utero to cocaine and cigarette smoke. Neonatal hair as a biological marker for fetal exposure in cocaine and nicotine has emerged as an excellent tool in correlating in utero exposure and outcome. However, a limiting factor is the sparsity of neonatal hair. We report on the first method that allows determination of both cocaine and nicotine as well as their metabolites in the same hair samples.
TL;DR: Recommendations for the routine monitoring of Cyclosporin-A are presented, including blood sampling methodological approaches and interpretation of results generated, intended to address the diversity of attitudes to CsA monitoring demonstrated in a recent national survey of Australian laboratories that provide C'sA analyses.
Abstract: Cyclosporin-A (CsA) therapeutic drug monitoring plays an integral role in therapeutic management of immunosuppressed patients, including those with organ transplants. This communication, prepared by an Australian team, presents recommendations for the routine monitoring of CsA, including blood sampling methodological approaches and interpretation of results generated. The consensus approach described is intended to address the diversity of attitudes to CsA monitoring demonstrated in a recent national survey of Australian laboratories that provide CsA analyses.
TL;DR: An automated column-switching method coupled to isocratic high-performance liquid chromatography has been developed for simultaneous determination of blood levels of paroxetine and its nonconjugated main metabolite BRL 36610, indicating drug interactions.
Abstract: An automated column-switching method coupled to isocratic high-performance liquid chromatography has been developed for simultaneous determination of blood levels of paroxetine and its nonconjugated main metabolite BRL 36610. The lower limits of detection were 9-15 nmol/L (3-5 ng/ml) and linearity between drug concentration and detector response was found for 0-1,500 nmol/L (0-500 ng/ml). The method could be applied to the analysis of serum samples obtained from depressed patients who were treated with daily oral doses of 20 or 40 mg of paroxetine. After the 20-mg dose, the mean blood level of paroxetine was 69 nM (23 ng/ml), whereas the metabolite BRL 36610 was detectable in only one of 5 samples. Co-medication of paroxetine with imipramine increased the blood levels of imipramine, desipramine, and paroxetine thus indicating drug interactions.
TL;DR: A reversed-phase high-performance liquid chromatographic (HPLC) method for the measurement of lamotrigine (LTG) simultaneously with phenobarbitone (PB), phenytoin (PHT), and carbamazepine (CBZ) is described using hexobarbital as the internal standard.
Abstract: A reverse-phase high-performance liquid chromatographic (HPLC) method for the measurement of lamotrigine (LTG) simultaneously with phenobarbitone (PB), phenytoin (PHT), and carbamazepine (CBZ) is described using hexobarbital as the internal standard. The method uses the chromophore at 307 nm to detect LTG in the presence of interfering CBZ-10,11-epoxide detected at 220 nm, the wavelength used to measure the other drugs. This method requires < 10 min/sample for completion. Simultaneous monitoring of the chromatographs at 220 and 310 nm with a simple calculation allows LTG to be measured virtually identically to a routine method for monitoring of the other anticonvulsants. Between-batch precisions for LTG at 2 and 6 mg/L were < 5%. Accuracy of LTG estimation was assessed by comparison with known values of samples supplied by an external quality assessment scheme.
TL;DR: A population analysis of the kinetics of lithium was performed from experimental and observational data in 113 subjects in order to propose a new approach for lithium dosage individualization, and a Bayesian approach for individualizing dosing schemes is proposed.
Abstract: SummaryA population analysis of the kinetics of lithium was performed from experimental and observational data in 113 subjects in order to propose a new approach for lithium dosage individualization. The kinetics of lithium is described by a two-compartment model. Age, body weight, height, and serum
TL;DR: The results suggest that sex-related differences in MEGX formation as well as the influence of contraceptives have to be taken into account when test results from living related liver donors and patients with less advanced chronic liver disease are evaluated.
Abstract: The objective of this study was to investigate the effect of gender on monoethylglycinexylidide (MEGX) formation in normal subjects and cadaveric liver donors. The study included 92 male and female healthy volunteers < 45 years of age and 98 age- and sex-matched liver donors from a previous study, whose livers were used for transplantation. Women < 45 years not taking contraceptives showed significantly lower MEGX concentrations 30 min after lidocaine administration than men [median (16-84th percentile)]: 59 micrograms/L (41-70 micrograms/L) versus 81 micrograms/L (58-98 micrograms/L)]. The lowest MEGX 30 min values were observed in women taking contraceptives: 39 micrograms/L (25-48 micrograms/L). Intraindividual variability of serial MEGX tests was moderate (median: 17.8%, n = 8) when measured in female subjects taking no contraceptives and males. Cadaveric liver donors showed significantly higher MEGX 15 and 30 min values compared with normal subjects (p < or = 0.0001). There was no statistically significant difference between MEGX values obtained in male and female cadaveric donors. The urinary excretion of MEGX was similar in male and female normal subjects. Our results suggest that sex-related differences in MEGX formation as well as the influence of contraceptives have to be taken into account when test results from living related liver donors and patients with less advanced chronic liver disease are evaluated. In cadaveric liver donors, however, sex-related differences do not affect MEGX formation.
TL;DR: Plotting cumulative percentages of patients with fully controlled seizures versus plasma antiepileptic drug concentrations yielded data that were broadly in keeping with conventional 'therapeutic' ranges for phenytoin, carbamazepine, phenobarbital, and ethosuximide monotherapy.
Abstract: Rates for being free of all epileptic seizures for at least 1 year and for ceasing therapy after 3–5 years of full seizure control were similar in 548 treated epileptic patients referred from 1962 to 1970, during which period plasma antiepileptic drug concentration monitoring became available (32.7 and 17.0%, respectively), in 960 patients referred from 1971 to 1979, when such monitoring was used increasingly (29.6 and 14.9%, respectively), and in 348 patients referred from 1980 to 1989, when this monitoring was widely available (30.5 and 10.1%, respectively). However, monitoring was associated with higher rates of full seizure control in patients seen within 6 months of their first seizure, even when patients with only a solitary seizure were excluded. Possibly, monitoring then helped achieve early complete suppression of not yet established seizure processes, but had less effect on already entrenched seizure mechanisms. Plotting cumulative percentages of patients with fully controlled seizures versus plasma antiepileptic drug concentrations yielded data that were broadly in keeping with conventional 'therapeutic' ranges for phenytoin, carbamazepine, phenobarbital, and ethosuximide monotherapy. With a given plasma phenobarbital (but not phenytoin or carbamazepine) concentration, rates of full seizure control were appreciably higher for generalized onset than for partial onset seizures. Use of a second antiepileptic drug was associated with improved full seizure control in both generalized onset and partial onset seizures, which had not been controlled by monotherapy; adding a third drug yielded little further benefit.
TL;DR: A three-step liquid-liquid extraction procedure following by reversed-phase chromatography and spectrofluorimetric detection was performed, and this assay allowed determination of 20 ng/ml of both itraconazole and its active metabolite with an acceptable precision using a 0.5-ml plasma sample.
Abstract: Itraconazole is a new triazole antifungal agent. Active orally, this drug is effective against a wide range of fungal pathogens that includes Aspergillus species, and its use in leukemic and AIDS patients is currently on the increase. Oral itraconazole absorption presents up to threefold interindividual variation in man and is reduced in AIDS patients. Consequently an individual itraconazole adjusting dosage is necessary to ensure adequate clinical antifungal activity. Itraconazole undergoes extensive metabolism and the main isolated metabolite, hydroxyitraconazole, is found in plasma at concentrations 2-3-fold higher than parent drug and presents in vitro the same antifungal activity. At present, despite the contribution of this metabolite to the overall activity of the drug, no well-documented assay was reported in the literature for the codetermination of itraconazole and hydroxyitraconazole in plasma. Due to the wide variety of coadministered drugs to patients receiving itraconazole, the purpose of the developed method was to obtain a specific assay sensitive enough for itraconazole therapeutic monitoring. Therefore, a three-step liquid-liquid extraction procedure following by reversed-phase chromatography and spectrofluorimetric detection was performed. This assay allowed determination of 20 ng/ml of both itraconazole and its active metabolite with an acceptable precision using a 0.5-ml plasma sample; no analytic interference was encountered from 45 coadministered drugs tested.
TL;DR: In individual patients, 6-TGN levels were relatively stable throughout the dosing interval (“within-dose-interval-CV” < 19%), even when sharp and high 6-MP peaks in plasma were observed.
Abstract: The purpose of this study was to examine the pharmacokinetics of mercaptopurine (6-MP) and thioguanine nucleotides (6-TGN) during azathioprine treatment. Plasma profiles and urinary excretion of 6-MP and 6-TGN concentrations in red blood cells (RBCs) were measured repeatedly during the first 3 weeks following transplantation in 10 adults, who had received kidney grafts from living related donors. Mean maximal 6-MP plasma concentration (Cmax) was 340 nmol/L (SD = 290), mean time to Cmax (Tmax) was 2 h (SD = 1.8), and mean area under the plasma concentration-time curve (AUC) was 930 nmol/L/h (SD = 770). The mean fraction of azathioprine dose excreted as 6-MP in urine was 1.32% (SD = 1.11). Up to eightfold variability of Cmax and AUC was observed from day to day within each patient. The correlation between 6-MP AUC and amount excreted in the urine was weak (r = 0.37, 95% CI from 0.02 to 0.64). In this group of patients the observed 6-TGN levels in RBCs were low; maxima during the observation period ranged from undetectable to 250 pmol/8 x 10(8) RBCs. In individual patients, 6-TGN levels were relatively stable throughout the dosing interval ("within-dose-interval-CV" < 19%), even when sharp and high 6-MP peaks in plasma were observed.
TL;DR: It is concluded that at the dosage used omeprazole does not increase the rate of oxidative and conjugative reactions involved in the metabolism of phenacetin and paracetamol respectively, consistent with the hypothesis that omepazole is generally devoid of inducing effects on CYP1A2 activity in vivo.
Abstract: Omeprazole has been reported to increase cytochrome P450IA2 (CYP1A2) activity in vitro, but whether this effect also occurs in vivo is controversial. To clarify this issue, the effect of omeprazole (20 mg/day for 8 days) on the kinetics and metabolism of phenacetin, an in vivo marker of CYP1A2 activity, was examined in 10 healthy volunteers. The pharmacokinetic parameters of phenacetin and metabolically derived paracetamol on the 8th day of omeprazole administration were very similar to those observed in a control session in the absence of omeprazole administration, the only significant difference being a higher peak plasma phenacetin concentration during omeprazole treatment. It is concluded that at the dosage used omeprazole does not increase the rate of oxidative and conjugative reactions involved in the metabolism of phenacetin and paracetamol respectively. These data are consistent with the hypothesis that omeprazole is generally devoid of inducing effects on CYP1A2 activity in vivo, at least in a Caucasian population with a low prevalence of the omeprazole-mephenytoin poor metabolizer phenotype.
TL;DR: After oral administration and collection of 24-h urine, this method allows the in vivo study of aminopyrine metabolism, which reflects liver function, and excellent linearity was obtained in the range 1–150 μg/ml urine, either for parent drugs and metabolites.
Abstract: A readily applicable and accurate isocratic high-performance liquid chromatography method for the detection of aminopyrine, dipyrone and its metabolites in urine is described. Parent drugs and four metabolites were chloroform-extracted from 1 ml of urine after addition of the internal standard isopropylaminoantipyrine and alkalinization. The organic phase was evaporated to dryness, and the residue was reconstituted in the mobile phase, which was injected onto a Spherisorb ODS 5 microns particle-size column (250 x 4.6 mm) using as mobile phase water, methanol, triethylamine, and acetic acid. The column eluent was monitored by ultraviolet absorption at 254 nm. Excellent linearity (r > 0.99) was obtained in the range 1-150 micrograms/ml urine, either for parent drugs and metabolites. This method offers a sensitive assay for aminopyrine, dipyrone (widely consumed in some countries) and its metabolites. After oral administration and collection of 24-h urine, this method allows the in vivo study of aminopyrine metabolism, which reflects liver function.
TL;DR: The results confirm that higher doses of CBZ can successfully be used in some patients with refractory partial epilepsy and confirm that the plasma level ofCBZ-E does not seem to be a useful indicator of toxicity in CBZ-treated ambulatory epileptic patients.
Abstract: We evaluated the efficacy, development of adverse effects, and possible correlation between the plasma concentration of carbamazepine (CBZ) and its major metabolite, carbamazepine-10,11-epoxide (CBZ-E), in a group of epileptic patients in whom selective increases in CBZ doses were made. Eighteen patients with refractory partial epilepsy participated in an open trial. Five were on monotherapy and 13 on polytherapy. All the patients were on CBZ before the trial and had plasma levels within the therapeutic range (17-42 mumol/L). After a baseline period, CBZ doses were progressively increased either to reach a 50% reduction in seizure frequency for 2 months or until side effects appeared. Thirty-nine percent of the patients had a 50% decline in seizure frequency, but only 17% improved for > 6 months. Mild or moderate side effects were observed in 78% of the patients. Side effects were correlated with CBZ plasma levels but not with CBZ-E plasma levels. Correlation between CBZ and CBZ-E plasma levels were found in the monotherapy group, but not in the polytherapy group. Our results confirm that higher doses of CBZ can successfully be used in some patients with refractory partial epilepsy. Furthermore, the plasma level of CBZ-E does not seem to be a useful indicator of toxicity in CBZ-treated ambulatory epileptic patients.
TL;DR: A reversed-phase high-performance liquid chromatographic (HPLC) method for the simultaneous determination of a new and promising anticancer drug, CdA, and its metabolite, 2-chloroadehine, in plasma and urine was developed and will be a useful tool for further investigations of the pharmacokinetics in patients treated with different routes of administration.
Abstract: A reversed-phase high-performance liquid chromatographic (HPLC) method for the simultaneous determination of a new and promising anticancer drug, 2-chloro-2'-deoxyadenosine (CdA), and its metabolite, 2-chloroadenine (CAde), in plasma and urine was developed. A solid-phase extraction procedure with guaneran as internal standard (IS) was used. Plasma (1 ml) or diluted urine (1/100) mixed with 1 ml of phosphate buffer (10 mM, pH 6.5) was applied on a C8 isolute cartridge, which was prewashed with acetonitrile and phosphate buffer. The cartridge was further washed with 2.5 ml of 1% acetonitrile/phosphate buffer and 2.5 ml of hexane/dichloromethane (50/50). The compounds were eluted from the cartridge with 2.5 ml 5% MeOH in ethyl acetate. Chromatographic separation was achieved on C18 column eluted isocratically with phosphate buffer (10 mM, pH 3.0) containing 11% MeOH and 7% acetonitrile, and ultraviolet (UV) detection at 265 nm. Recoveries of CdA and CAde at 100 nmol/L were 90.6 +/- 4.9 and 98.7 +/- 7.8%, respectively. Recovery of IS was 96.1 +/- 6.1% at 250 nmol/l. The inter- and intraday coefficients of variation (CV) were < 10% at different concentrations within the range 1-500 nmol/L for both substances. In plasma, limits of detection of CdA and CAde were 1 and 2 nmol/L, respectively. In urine, the limit of detection was 100 nmol/L for both compounds. Standard curves were linear up to 50 and 500 nmol/L for urine and plasma, respectively. The present method will be a useful tool for further investigations of the pharmacokinetics of CdA in patients treated with different routes of administration.