摘要:

Summary:The enantioselectivity of hydroxylation of nortriptyline (NT) toE-10-hydroxynortriptyline (E-10-OH-NT) was studied in human liver microsomes, intestinal homogenate, and patients treated with NT. The rate of formation of (-)-E-10-OH-NT was higher than that of (+)-E-10-OH-NT both in the liver microsomes and in the intestinal homogenate. Quinidine, a prototype competitive inhibitor of the cytochrome P450IID6 (“debrisoquin hydroxylase”), inhibited the formation of (-)-E-10-OH-NT in a concentration-dependent manner in liver microsomes, while the formation of (+)-E-10-OH-NT was hardly affected. This indicates that P450IID6 catalyzes the hydroxylation of NT in a highly enantioselective manner to (-)-E-10-OH-NT in the liver. Another P450 isozyme besides IID6 seems to be responsible for the formation of the (+)-enantiomer in the liver. In intestinal homogenate, the formation of both enantiomers ofE-10-OH-NT was inhibited to about the same extent by quinidine, the maximum inhibition being much less than in the liver. In the urine of six patients treated with NT, the (-)-enantiomer accounted for 91 ± 2% of the unconjugatedE-10-OH-NT, and for 78 ± 6% of the glucuronide conjugates. The study shows that NT is hydroxylated in a highly enantioselective way, probably catalyzed by the polymorphic P450IID6, to (-)-E-10-OH-NT both in vitro in human liver as well as in vivo in patients treated with the drug.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The population pharmacokinetics of theophylline were studied in 35 neonates receiving aminophylline suppositories for the treatment of apnoea of prematurity. Routinely measured theophylline serum concentrations (n = 138, range 3–20 mg/L) were modelled in NONMEM according to a one-compartment model. The influence of a number of clinical and demographic factors, e.g., weight (range 0.8–2.5 kg) and postnatal age (2–80 days), on clearance/bioavailability (CL/F) and volume/bioavailability (V/F) was investigated. Both these parameters were found to significantly correlate to weight alone in a directly proportional manner:CL/F= 40 ± 2 ml/h/kg andV/F= 1.3 ± 0.2 L/kg. The absorption was best described by a first-order process, having a half-life of 1.6 ± 0.7 h. The interindividual variability inCL/Fwas 25%, whereas the same estimates inV/Fand in the first-order absorption rate constant could not be obtained. The residual variability in theophylline concentrations was modelled with additive error with an estimated standard deviation of 1.78 mg/L. From these results, it was concluded that rectal administration of aminophylline in neonates is a therapeutically acceptable alternative to oral administration. The convenience gained by rectal, compared to oral, administrations may compensate, in many instances, for the possibly slightly higher variability inCL/Fof the former.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:Steady-state plasma carbamazepine (CBZ) concentrations were measured in 196 pediatric inpatients taking CBZ alone or CBZ combined with other drugs. The steady-state CBZ concentrations divided by the daily administered dose (dose ratio, reciprocal of apparent clearance) increased significantly (r= 0.183,p> 0.01) with age. The correlation between dose and CBZ concentration, while significant (r= 0.265,p= 0.023), was weak because of wide interindividual differences in dose ratio. There was a negative correlation between CBZ daily dose and CBZ dose ratio. This negative correlation was significant in children 4–6 (r2= 0.481,p> 0.01), 7–11 (r2= 0.399,p> 0.01), and < 11 years of age (r2= 0.401,p> 0.01), but not in children > 4 years of age (r2= 0.172,p< 0.1). The CBZ dose ratio was significantly (p> 0.001) lower in patients taking CBZ in combination with more than one other antiepileptic drug compared with those on CBZ monotherapy. No significant (p< 0.1) difference in CBZ dose ratio was found between male and female patients. These findings suggest that CBZ clearance was influenced by age, dose, and comedication with more than one other antiepileptic drug but not sex. The concentration necessary for efficacy is a clinical, not an analytical decision. However, the dose-concentration relationships show that recommended pediatric CBZ doses of 10–30 mg/kg/day are not enough to attain published therapeutic CBZ concentrations in many children. Increases in CBZ doses to<30 mg/kg/day may be required even in children on monotherapy. However, prospective studies of the efficacy and toxicity of this regimen are required before it can be recommended.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The use of the angiotensin-converting enzyme inhibitor captopril in infants with congestive heart failure (CHF) has been empirical owing to a lack of relevant pharmacokinetic data. To determine standard pharmacokinetic parameters for the drug in this population, we administered captopril, 1 mg/kg, orally to 10 infants aged 6.8 ± 4.6 months. Sequential plasma unchanged and total (sum of unchanged and dimerized) captopril concentrations were determined using a high-performance liquid chromatographic method. Arterial pressure, systemic and pulmonary resistance, heart rate, and respiratory rate were all significantly decreased 1 h after the first dose of captopril. Plasma renin activity was not significantly increased. For unchanged captopril, the maximum concentration (Cmax) was 350 ± 184 ng/ml; the time toCmax(Tmax), 1.6 ± 0.4 h; elimination half-life (t1/2), 3.3 ± 3.3 h; oral clearance (Clo), 1.1 ± 0.4 L/h/kg. For total captopril,Cmaxwas 1,088 ± 621 ng/ml;Tmax, 2.7 ± 1.1 h;t1/2, 3.4 ± 1.0 h. Thus, we conclude that the pharmacokinetic parameters for captopril in infants with CHF are within the range reported for adults with CHF. Also, the hemodynamic changes, measured 1 h after the first dose, indicate that the acute effects of captopril in infants with CHF are beneficial.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:Digoxin is an important drug in the treatment of patients with either congestive heart failure or atrial arrhythmia. Because of its narrow therapeutic range, digoxin serum concentrations are commonly monitored in both inpatients and outpatients. However, with the costs of health care skyrocketing, there is debate whether such therapeutic drug monitoring (TDM) is cost-effective. To reduce the number of samples drawn too soon after a previous dose and in an effort to improve digoxin TDM at this teaching hospital, a new dosing and monitoring policy was initiated. This policy involved uniform digoxin dosing at 5 p.m. (1700 h) for all inpatients and serum drug measurements at 7 a.m. (0700 h) the next day. By coordinating the time of dosing to be < 12 h prior to serum digoxin analysis, the number of inappropriate digoxin serum determinations have been reduced. This new protocol has increased the effectiveness of the toxicology laboratory and enhanced the efficiency of the house staff. Other issues concerning digoxin TDM are also addressed. These findings can be generalized to all drugs that are monitored at any hospital and can result in a significant cost savings and decrease the time spent analyzing inappropriate data.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:A simple, selective, sensitive, and rapid high-performance liquid chromatography (HPLC) method is described for the quantitation of 6-mercaptopurine (6-MP) in plasma of patients with acute lymphoblastic leukemia (ALL). Pharmacokinetic data are presented for seven children with ALL receiving 6-MP therapy. A sensitivity of ≤2 ng/ml in plasma was achieved on a reverse-phase octadecylsilane column using an HPLC system following a cleanup step with a solid-phase extraction cartridge. The chromatogram was monitored at 325 nm. Analytical recovery of 6-MP was 90%. The coefficients of variation for intra-and interday variabilities were 2.51 and 4.23%. This assay method is clinically useful for pharmacokinetic studies of 6-MP in ALL patients.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:This article describes a high-performance liquid chromatography (HPLC) method for the simultaneous determination of morphine (M) and its principal metabolites morphine-3-glucuronide (M3G), morphine-6-glucuronide (M6G), and normorphine (NM) in plasma. All four compounds are extracted from plasma using a C8 solid-phase extraction column, separated by reverse-phase HPLC on a C18 analytical column, and detected by spectrofluorometry at 210 nm excitation wavelength. The method takes advantage of the compounds' native fluorescence, so that derivitization is not required. Samples have been quantified over a concentration range of 25–100 ng/ml M and NM, 50–200 ng/ml M3G, and 100–300 ng/ml M6G, using nalorphine (500 ng/ml) as internal standard. Within-run and between-run errors were > 10% for morphine and > 13% for all the metabolites. The lower limit of quantitation for morphine is 10 ng/ml. The accuracy of the method was confirmed by including quality controls fitted to the standard curves of each compound. The assay described in this article represents a simplification of previous versions of the method, which included cumbersome extraction procedures and multiple detectors. For the first time, an internal standard has been employed. The assay is reliable and easy to use and can be performed in any therapeutic drug monitoring laboratory.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:In the last decade, kits using dry chemistry have been introduced for analysis of theophylline in biological fluids. We investigated the performance of Ames Seralyzer and Kodak Ektachem 700XR. They were compared to an enzyme immunotechnique (Syva EMIT) and high-performance liquid chromatography (HPLC). Mixed sera from theophylline-treated patients at concentrations of 20, 50, and 80 μmol/L were used. We also investigated the performance of the various methods when assaying theophylline concentrations obtained from individual patients treated or intoxicated with theophylline (n = 35 patients). In within-day analysis, the EMIT method deviated + 1±9%, the Ektachem 700XR method deviated +2±8%, and the Seralyzer method deviated at least +18% compared to HPLC. Within-day variability was low for all 4 methods. A similar pattern was seen during between-day assay. In five intoxicated patients, EMIT, Seralyzer and Ektachem 700XR deviated at least +10% compared to HPLC. The Ektachem 700XR method deviated +16±36% compared to HPLC, when samples at 240 μmol/L and above were analyzed. Our study shows that theophylline assay kits cannot be recommended in drug analytical laboratories unless specific backup methods are available. EMIT showed the best performance compared to HPLC. Ektachem 700XR gave good results at therapeutic drug concentrations, but was not reliable in intoxicated patients or in those with decreased kidney function.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:The effect of serum separator tubes (SSTs) on free and total serum phenytoin and carbamazepine concentrations was determined by comparing standard no-additive tubes with SSTs (Becton Dickinson SST and Terumo Autosep). The influence of time prior to centrifugation, sample volume, and initial drug concentration on the effects were also studied. Results were analyzed using repeated measures two-way analysis of variance with tube type and either time, sample volume, or concentration as main effects. The most significant reductions noted were with Becton Dickinson SSTs in free and total serum phenytoin and total carbamazepine concentrations, where all reductions were > 10%. The only factor to significantly influence extent of reduction was the effect of time on total serum phenytoin concentration in Becton Dickinson SSTs. Terumo Autosep tubes caused no major reductions in free or total phenytoin or carbamazepine serum concentrations. Autosep tubes should provide accurate measurements of total and free serum phenytoin and carbamazepine concentrations. With Becton Dickinson SSTs, the reductions noted in free and total phenytoin and total carbamazepine concentrations were not large enough to preclude their clinical use. Becton Dickinson SSTs should not be used for determining free or total phenytoin or total carbamazepine concentrations for purposes of research.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Summary:We describe the use of a new form of solid-phase material, the Empore solid-phase extraction membrane (SPEM), for therapeutic drug monitoring. We evaluated the new extraction procedure with the companion high-performance liquid chromatographic (HPLC) method for the antiarrhythmic drug amiodarone and its metabolite, desethylamiodarone, in patients' serum. Acidified serum (250 μl) was passed through an octyl (C8) SPEM secured in an MF-1 microfilter unit. Serum proteins and potential interferences were removed with an acetonitrile: water wash, and the retained drugs eluted with HPLC mobile phase. This eluate was injected directly onto the analytical column. Both drugs averaged 85% recovery with a linear response from a lower limit of detection at 0.05 mg/L up to 6 mg/L, and between-run precision coefficients of variation ranging from 3.1 to 6.4% over the concentration range of 0.5–3.0 mg/L. We observed significant advantages of the novel SPEM over conventional liquid-liquid or large-particle size solid-phase sorbents packed in cartridges. Minimal amounts of solvents were required, elution volume was smaller, time-consuming evaporating/concentrating steps that can influence drug stability were avoided, and little throw-away material was generated. Only the small membrane was discarded.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID