Elimination of amrinone during continuous veno-venous haemofiltration after cardiac surgery

We studied the elimination of amrinone during continuous veno-venous haemofiltration (CVVHF) in three anuric patients after cardiac surgery. The patients had developed low cardiac output followed by acute prerenal failure. Plasma amrinone levels measured by HPLC were fitted to a two-compartment model.We found significant amrinone clearance, with a mean sieving coefficient (S) of 0.44%, which correlates with the protein-unbound, pharmacologically effective fraction of amrinone. The AUC of the arterial plasma concentration-time curve was decreased by 49.8%. All pharmacokinetic parameters showed wide interindividual variation.To ensure the therapeutic effect of amrinone and to avoid toxic adverse effects monitoring of plasma amrinone levels is necessary.     

Pharmacokinetics of mezlocillin and sulbactam under continuous veno-venous hemodialysis (CVVHD) in intensive care patients with acute renal failure

Objective: In intensive care medicine, continuous detoxication methods, such as continuous veno-venous hemodialysis (CVVHD), are used for treating acute renal failure. However, in contrast to conventional hemodialysis, little is known about the pharmacokinetics of many drugs administered in this setting and guidelines for dosages of drugs often do not exist. This holds particularly true for broad-spectrum antibiotics, which are often required during intensive care. Methods: In this study, we investigated the pharmacokinetics of the acylureidopenicillin mezlocillin and the β-lactamase inhibitor sulbactam during CVVHD and deduced dosage recommendations from the kinetic parameters with the goal of maintaining trough levels of above 10 mg · l⁻¹ for mezlocillin and 5 mg · l⁻¹ for sulbactam. Six intensive care patients with acute renal failure, receiving mezlocillin (n=5) and/or sulbactam (n=4), were examined during CVVHD and during intervals between CVVHD. The serum concentrations and the amounts of the drugs excreted into the dialyzate and into the urine within one dosage interval were measured using high performance liquid chromatography (HPLC). Three of the patients were jaundiced, indicating functional impairment of the liver. Results: The clearances by CVVHD (CL_CVVHD) for mezlocillin ranged between 11.0 and 44.9 ml · min⁻¹ and the half lives ranged between 1.12 and 8.84 h. Low CL and long half lives were observed in the patients with jaundice. For sulbactam, CL_CVVHD ranged between 10.1 and 22.8 ml · min⁻¹ and serum half lives were 4.25–6.11 h, independent of liver function. Conclusion: Due to high hepatobiliary clearance of mezlocillin, dosage adjustments in patients with acute renal failure, treated by CVVHD, are needed only with concurrent impaired liver function. For sulbactam, the optimal dose was found to be 0.5 g, administered every 12 h, regardless of liver function. Received: 25 February 1997 / Accepted in revised form: 21 May 1997     

连续性静脉-静脉血液滤过患者血清中利奈唑胺的浓度监测

目的:对连续性静脉-静脉血液滤过(continuous venovenous hemofiltration,CVVH)治疗的危重患者进行利奈唑胺血药浓度监测,为临床个体化治疗提供依据。方法:建立高效液相色谱法(以左氧氟沙星为内标),测定患者血清中利奈唑胺谷浓度。结果:利奈唑胺在0.31～20.00μg.mL-1内线性关系良好(r=0.999 5),定量限为0.31μg.mL-1。5例危重患者在治疗期间监测23次的利奈唑胺谷浓度变化明显,变化范围为1.53～17.10μg.mL-1。有2例患者谷浓度变化较大(相差近5倍)。结论:高效液相色谱法简单、快速、准确、灵敏、重复性好,可用于临床利奈唑胺的血药浓度监测。进行连续性静脉-静脉血液滤过治疗的患者,应用利奈唑胺时血药浓度变化较大,需要通过治疗药物监测的方法制定个体化给药方案。     

Pharmacokinetics and dialysability of isradipine in chronic haemodialysis patients

Summary The pharmacokinetics of isradipine, a calcium-channel blocker, have been studied in eight patients on chronic haemodialysis. A single oral dose of 5 mg was administered on both a non-haemodialysis and a haemodialysis day and the plasma concentrations of isradipine were analyzed.The mean c_max, t_max, AUC, and t_1/2 in plasma on the non-haemodialysis day were 5.2 ng·ml^–1, 1.4 h, 23.8 ng·h·ml^–1, and 3.1 h, respectively. The dialysis clearance of isradipine was negligible (5.0 ml·min^–1).The t_1/2 values during haemodialysis were not significantly different from those observed during the same period post dose on the non-haemodialysis day. The study demonstrates that supplemental doses of isradipine are not necessary in these patients since isradipine is not significantly removed by haemodialysis.     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

Lack of a kinetic interaction between fluconazole and mexiletine

Objective. To investigate the effect of fluconazole on the kinetics of mexiletine. Methods. Six healthy male volunteers participated in a crossover study. On the 1st day, the subjects received 200 mg mexiletine alone. On days 2–7 they received 200 mg fluconazole orally, and on day 8 they received 200 mg mexiletine and 200 mg fluconazole concomitantly. In a third phase two subjects received 400 mg fluconazole daily. Results. No differences in concentrations were observed between the three phases. The area under the concentration curves (AUC) after administration of mexiletine alone and in combination with fluconazole 200 mg/day were 6.63 and 7.31 μg ⋅ h ⋅ ml⁻¹, respectively. Conclusion. These findings suggest that fluconazole does not inhibit mexiletine metabolism. Received: 7 July 1995/Accepted in revised form: 19 September 1995     

Effect of fluconazole on theophylline disposition in humans

The effect of fluconazole, an antimycotic that inhibits cytochrome P-450-mediated drug metabolism, on theophylline kinetics and the production of its metabolites were compared with those of enoxacin in 5 healthy subjects. All subjects received a single oral dose of 240 mg theophylline (aminophylline, 300 mg) after they had been given oral fluconazole 100 mg every 12 h or enoxacin 200 mg every 8 h for three consecutive days.Pretreatment with enoxacin decreased the total clearance (CL_T) and elimination rate constant (K_el) of theophylline by 50% and 46%, respectively, without changing the volume of distribution (V_d), but there were no significant change in any pharmacokinetic parameter when fluconazole was administered. Enoxacin led to a 50% reduction in the metabolic clearance (CL_M) of theophylline and to decreases of 69%, 59% and 38% in the formation clearance of the three theophylline metabolites, 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU), respectively, accompanied by significant changes in the urinary recovery of theophylline and its metabolites. In contrast, treatment with fluconazole led only to a slight decrease in the CL_M of theophylline (16%) and in the formation clearance of its metabolites (15%–18%), and there was no change in the renal clearance (CL_R) of theophylline.The results indicate that fluconazole is a minor inhibitor of theophylline disposition compared with enoxacin, and they suggest that the inhibitory action of fluconazole is selective for certain cytochrome P-450 isozymes, but not for the cytochrome P-4501A involved in theophylline metabolism.     

Pharmacokinetics of ganciclovir in a patient undergoing chronic haemodialysis

The pharmacokinetics of ganciclovir was evaluated in a 73-year old anuric, haemodialyzed patient given 1.25 mg·kg^-1 at the end of each haemodialysis session, three times per week.A biexponential decrease in plasma ganciclovir was observed, with a peak concentration of 3.7 mg·1^-1 followed by a steady state value of 2.6 mg·1^-1 for almost 40 h. The total plasma clearance was 0.05 ml·min^-1·kg^-1, the volume of distribution at steady state was 0.61·kg^-1, the elimination half life was 132 h, the area under curve was 372 g·h·ml^-1, the mean residence time was 190 h, and the percentage of ganciclovir cleared from plasma after a 5 h haemodialysis session was 52.1%.The simulated pharmacokinetics over one month, following the same scheme of administration, did not suggest marked accumulation of ganciclovir. These results were obtained after a reduction of 58% in the recommended dose in patients with impaired renal function.     

Relationship between 5-fluorouracil exposure and outcome in patients receiving continuous venous infusion with or without concomitant radiotherapy

AIMS: Toxicity and response are correlated with plasma 5-fluorouracil (5-FU) concentration in patients treated with 5-FU at a dose of 1000 mg m(-2) day(-1). Head and neck cancer patients are treated with various therapeutic regimens, including chemotherapy with 5-FU at a dose of 600 mg m(-2) day(-1) with radiotherapy. We investigated the plasma concentration-effect relationship for this regimen, with the aim of developing recommendations for dose adjustment. METHODS: Patients received 5-FU at doses of 600 or 1000 mg m(-2) day(-1), as a continuous infusion over 4 or 5 days, with or without radiotherapy for the 600 mg m(-2) day(-1) regimen. The area under the curve (AUC) for 5-FU concentration was estimated, based on a single morning blood sample taken each day during treatment. AUC values were compared between patients with and without toxicity. This simplified method for AUC estimation was compared with the standard two-samples-per-day method in an independent group of 50 patients. RESULTS: Forty-six patients, corresponding to 115 courses, were included in this prospective study. Considerable interindividual variability in estimated AUC was observed for both doses. Grade 3-4 toxicity occurred in 10 and 21% of patients given doses of 600 and 1000 mg m(-2) day(-1), respectively. Ths study confirmed the relationship between plasma 5-FU concentration and toxicity previously reported for 1000 mg m(-2) day(-1), but found no such relationship for the 600 mg m(-2) day(-1) regimen with concomitant radiotherapy. CONCLUSIONS: Our results do not support the use of therapeutic drug monitoring to improve tolerance for the 600 mg m(-2) day(-1) regimen with concomitant radiotherapy. A simplified method is proposed for 5-FU monitoring for the 1000 mg m(-2) day(-1) regimen.     

Recrystallization of fluconazole using the supercritical antisolvent (SAS) process

The supercritical antisolvent (SAS) process was used to modify solid state characteristics of fluconazole. Fluconazole was recrystallized at various temperatures (60-80 degrees C) and pressures (8-16MPa) using dichloromethane (DCM) as a solvent. Acetone and ethanol were also employed as solvents. The fluconazole polymorphs prepared by the SAS process were characterized by differential scanning calorimetry (DSC), thermogravimetry analysis (TGA), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Furthermore, the equilibrium solubility of the samples in aqueous solution was determined. Fluconazole anhydrate form I was obtained at low temperature (40 degrees C) and anhydrate form II was obtained at high temperature (80 degrees C). The variation of pressure during the SAS process may influence the preferred orientation. Anhydrate forms I and II were also obtained using various solvents. Therefore, it was shown that solid state characteristics of fluconazole, including the polymorphic form and preferred orientation, can be controlled by changing operating conditions of the SAS process such as temperature, pressure, and solvent.     

Pharmacokinetics of tocainide in patients with renal dysfunction and during haemodialysis

Summary The disposition of tocainide was studied in 15 patients with renal dysfunction. In 9 with total renal failure, the plasma half-life ranged from 16.6 to 42.7 h and total plasma clearance from 35 to 94 ml/min. The longest half-lives were found in 1 patient with cirrhosis, 3 taking the enzyme inhibitor allopurinol, and 1 on cimetidine. The mean half-life in the remaining patients was 22.3±4.8 h (±SD). During a 4 h haemodialysis, the half-life in the 9 patients decreased to 8.5±4.6 h, which was calculated to correspond to removal of 25±14% of the drug from the body. In 6 patients with impaired renal function (creatinine clearance 10–55 ml/min) the tocainide half-life ranged from 13.2 to 22.0 h and total plasma clearance from 72 to 122 ml/min. One patient was taking allopurinol and 1 dihydralazine, and the mean half-life in the others was 19.2±4.0 h. The apparent volume of distribution was similar to that found previously in healthy subjects. The results suggest that tocainide elimination is predictably reduced in patients with renal disease.     

Pharmacokinetics of midazolam during continuous infusion in critically ill neonates

Summary Midazolam is a water soluble benzodiazepine, with a short elimination half-life in adults and children. An IV bolus (0.2 mg·kg^–1) immediately followed by continuous infusion of 0.06 mg·kg^–1·h^–1 was administered to 15 critically ill neonates at a gestational age of 32.8 weeks, who required sedation for mechanical ventilation. Heart rate and blood pressure were closely monitored.Hypotension occurred in 4 patients after the bolus dose or during the continuous infusion. Three of them had also been given fentanyl. Individual pharmacokinetic parameters were calculated: plasma clearance was 3.9 ml·min^–1, elimination half-life was 12.0 h. Because of its short half-life compared to diazepam, midazolam may be used during the neonatal period to achieve rapid, brief sedation. However, it should be administered cautiously to neonates, particularly in premature infants, or if fentanyl is also given.     

Multiple dose kinetics of ofloxacin and ofloxacin metabolites in haemodialysis patients

Summary 7 patients with end-stage renal disease on regular haemodialysis were treated orally with a loading dose of 200 mg ofloxacin and multiple maintenance doses of 100 mg per 24 h for 10 days. The pharmacokinetics of ofloxacin and its metabolites were studied at the end of the treatment period. Plasma and dialysate concentrations of ofloxacin and ofloxacin metabolites were measured by HPLC.Peak (3.1 mg·1^–1) and trough levels (1.6 mg·1^–1) and the AUC of ofloxacin were comparable to the values in healthy volunteers given 300 to 400 mg ofloxacin p.o. The mean half-life, determined in the dialysis-free interval (t_1/2) and during the haemodialysis session (t_1/2HD), was 38.5 h and 9.9 h, respectively. Extrarenal clearance (32.7 ml·min^–1) was unchanged as compared to that reported in healthy volunteers after a single dose of ofloxacin. The fractional removal by haemodialysis amounted to 21.5%. Two metabolites, ofloxacin-N-oxide and demethyl-ofloxacin, were detected in plasma. Despite prolonged t_1/2 of both metabolites (66.1 and 50.9 h) and multiple doses of ofloxacin the peak concentrations of the metabolites reached only 14% and 5% of that of the parent drug, respectively.It is concluded that in patients on regular haemodialysis treatment the dosage adjustment employed resulted in safe and therapeutically favourable plasma concentrations. The observed accumulation of ofloxacin metabolites does not appear to have any toxic or therapeutic significance.     

Influence of fluconazole on the pharmacokinetics of omeprazole in healthy volunteers

Influence of fluconazole on the pharmacokinetics of omeprazole was evaluated by single oral administration of omeprazole capsule 20 mg (control group), or single oral administration of fluconazole capsule, 100 mg, and omeprazole, 20 mg, after 4 days of daily oral administration of fluconazole, 100 mg (treated group), to 18 healthy male volunteers. Omeprazole is extensively metabolized in the liver through 5-hydroxylation and sulfoxidation reactions catalyzed predominantly by CYP2C19 and CYP3A4, respectively. Fluconazole is a potent competitive inhibitor of CYP2C19 and a weak inhibitor of CYP3A4. In treated group, the area under the plasma concentration-time curve of omeprazole from time zero to time infinity (AUC) was significantly greater (3090 vs 491 ng h/ml), terminal half-life of omeprazole was significantly longer (2.59 vs 0.85 h), and peak plasma concentration of omeprazole (C(max)) was significantly higher (746 vs 311 ng/ml) than that in control group. The greater AUC and higher C(max) in treated group could be due to inhibition of omeprazole metabolism by fluconazole.     

中国汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学考察

目的研究汉族和朝鲜族健康志愿者单剂量口服氟康唑片的药物动力学。方法健康汉族和朝鲜族受试者各10名,男女各半,口服氟康唑片200 mg,定时采血,用RP-HPLC法测定血药质量浓度,用drug and statistics(DAS 2.0.1)软件程序进行数据处理,用SPSS软件程序进行统计分析。结果汉族和朝鲜族受试者主要药物动力学参数ρmax为(4.91±0.67)、(4.70±0.86)mg.L-1;tmax为(1.90±0.90)、(2.55±1.07)h;t1/2为(33.07±5.90)、(31.02±6.02)h;AUC(0-96)为(189.61±32.91)、(183.75±31.83)mg.h.L-1,AUC(0-∞)为(219.21±40.46)、(209.93±46.37)mg.h.L-1。统计结果显示两民族受试者主要药物动力学参数差异无统计学意义。结论汉族、朝鲜族两民族的种族差异对氟康唑片的药物动力学无影响。     

妊娠期癫痫患者左乙拉西坦药动学行为变化

目的：系统研究左乙拉西坦（levetiracetam,LEV）在妊娠期癫痫患者体内药动学行为变化,并探究基于LEV血药浓度监测,调整妊娠期癫痫患者的给药方案。方法：回顾性收集2017年1月至2021年7月于中国医科大学附属盛京医院就诊并进行LEV血药浓度监测的妊娠期癫痫患者的临床病历资料,计算孕前至产后LEV的表观清除率（CL）,分析妊娠期癫痫患者LEV的给药方案,并探究妊娠期合并用药对LEV体内药动学行为的影响。结果：对17例单用LEV治疗的妊娠期癫痫患者138次血药浓度监测数据的回顾性分析表明,妊娠期LEV的CL显著增加,与孕前基线相比,在妊娠早期、中期及晚期分别增加了86.39%（P<0.01）、148.30%（P<0.01）和134.69%（P<0.01）,分娩后迅速下降,于产后6周左右恢复至孕前水平。不同妊娠时期LEV给药剂量存在差异,妊娠中、晚期给药剂量较孕前分别增加了44.93%（P<0.01）和96.07%（P<0.01）。妊娠期合用具酶诱导作用的抗癫痫药能够诱导LEV代谢,使LEV的CL增加。结论：妊娠期癫痫患者LEV体内药动学行为变化显著,其CL于妊娠中期达到峰值,分娩后迅速降低。与具酶诱导作用的抗癫痫药合用会增加LEV的CL。定期监测LEV血药浓度可为妊娠期癫痫患者的药物治疗管理提供指导。