Garenoxacin pharmacokinetics in subjects with renal impairment*

ABSTRACT

Objective: This open-label, parallel-group study determined the pharmacokinetics of garenoxacin in subjects with severe renal impairment, including subjects maintained on dialysis.

Research design and methods: Subjects were assigned to one of four groups according to their underlying renal function: creatinine clearance (CL_cr) > 80?mL/min, CL_cr < 30?mL/min, hemodialysis (HD), and continuous ambulatory peritoneal dialysis (CAPD). Subjects received a single oral 600?mg dose of garenoxacin. Administration of garenoxacin to subjects receiving hemodialysis was completed in two phases separated by 14 days: 3?h before HD (phase 1) and immediately after HD (phase 2).

Main outcome measures: Plasma and urine or dialysate samples were analyzed for garenoxacin, and single-dose pharmacokinetic parameters were estimated. Safety was assessed.

Results: Twenty-five subjects received garenoxacin. Compared with healthy controls, garenoxacin area under the concentration–time curve (AUC) and maximum plasma concentration were increased by 51% and lowered by 20%, respectively, in subjects with severe renal impairment. The terminal half-life was prolonged in subjects with severe renal impairment compared with healthy controls (26.5 ± 7?h vs 14.4 ± 3?h, respectively). In subjects receiving HD or CAPD, removal of garenoxacin from systemic circulation was relatively inefficient (HD, 1.5–11.5%; CAPD, 3%), suggesting no need for a supplemental dose of garenoxacin after dialysis. Garenoxacin was well tolerated.

Conclusions: Based on the broad therapeutic index of garenoxacin, the effects of renal impairment on garenoxacin exposure are not considered clinically significant. There was a modest increase in AUC in subjects with severe renal impairment and the magnitude of the changes was not considered clinically relevant.     

Single-dose pharmacokinetics of temocapril and temocapril diacid in subjects with varying degrees of renal impairment

Objective: The aim of this study was to determine the influence of renal impairment on the single-dose pharmacokinetics of temocapril and its pharmacologically active metabolite, temocapril diacid. Methods: A single oral dose of 20?mg temocapril hydrochloride was given after an overnight fast to eight healthy (control) subjects (group A, n=8) with a mean baseline creatinine clearance (CL_CR) of 115.2?ml?·?min^?1 and to three groups of patients with decreased renal function (mean CL_CR 56.9?ml in group B, n=8, 30.0?ml?·?min^?1 in group C, n=8 and 15.4?ml?·?min^?1 in group D, n=5). Results: The mean peak concentration and median time to peak concentration for both temocapril and its diacid metabolite as well as the mean area under the curve (AUC_0∞) for temocapril did not differ significantly between groups. The mean AUC_0∞ for temocapril diacid increased only two- to threefold from group A to D. The mean terminal elimination half-life (t½) for temocapril diacid was prolonged in subjects with impaired renal function. However, prolongation of mean t½ and increase in AUC_0?∞ did not parallel the decrease of mean renal clearance for temocapril diacid. Conclusion: The results suggest the existence of an alternative pathway in addition to the renal excretion of temocapril, e.g. via the bile. This pathway substantially contributes to the elimination of the active metabolite, temocapril diacid, in patients with decreased renal function. Nonetheless, to avoid any risks, the dose of temocapril hydrochloride in patients with moderate to severe renal impairment should be reduced.     

Disposition kinetics of disopyramide in patients with renal insufficiency

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (β) was related to the endogenous creatinine clearance (Cl_cr). However, a decrease in β was not observed until the Cl_cr was reduced below 40 ml min^?1. Below 40 ml min^?1 a linear relationship existed between β and Cl_cr. Similarly, the plasma elimination half-life (t_½β) showed a significant increase when the Cl_cr was less than 30 ml min^?1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two-thirds of that in normal subjects. Therefore, in patients with Cl_cr less than 40 ml min^?1 both the loading and maintenance dose of disopyramide should be reduced.     

Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate renal impairment

Aims

To evaluate the pharmacokinetics and pharmacodynamics following a single dose of liposomal mifamurtide (L-MTP-PE, MEPACT®) in adult subjects with mild (calculated creatinine clearance [CL_cr] of 50–80 ml min⁻¹) or moderate (CL_cr 30–50 ml min⁻¹) renal impairment in comparison with age-, weight- and gender-matched healthy subjects with normal renal function (CL_cr >80 ml min⁻¹).

Methods

Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for analysis of plasma pharmacokinetics of total and non-liposome-associated (free) mifamurtide and assessment of pharmacodynamics (changes in serum interleukin-6 [IL-6], tumour necrosis factor-α [TNF-α], C-reactive protein [CRP]).

Results

Thirty-three subjects were enrolled: nine with mild renal impairment, eight with moderate renal impairment and 16 healthy subjects. Geometric mean (%CV) AUC_inf for total mifamurtide was 89.5 (58.1), 94.8 (27.8), 85.1 (29.0), 95.4 (18.1) nm h in the mild renal impairment, mild-matched healthy subject, moderate renal impairment and moderate-matched healthy subject groups, respectively. Mifamurtide clearance was not correlated with CL_cr, estimated glomerular filtration rate or iohexol clearance (all r² < 0.01). AUC_inf of free mifamurtide was similar across the renal function groups. There were no readily apparent differences in serum pharmacodynamic effect parameters (baseline-adjusted AUEC_last for IL-6 and TNF-α and E_max for CRP) between the renal function groups. No subjects reported grade ≥3 or serious adverse events.

Conclusions

Mild or moderate renal impairment does not alter the clinical pharmacokinetics or pharmacodynamics of mifamurtide. No dose modifications appear necessary for these patients based on clinical pharmacologic considerations.     

肾功能亢进患者万古霉素血药浓度监测与临床疗效分析

目的：调查分析肾功能亢进（augmented renal clearance, ARC）患者使用万古霉素的用药剂量、谷浓度及临床疗效。方法：回顾性研究2013年7月-2017年3月在某院住院期间使用过万古霉素并进行了血药浓度监测的67例ARC患者和142例肾功能正常患者病历资料,比较2组万古霉素给药方案、谷浓度及临床疗效。结果：ARC组与肾功能正常组初始给药的日剂量分别为（2.0±0.3） g和（1.8±0.4） g,具有显著性差异（P=0.041）。ARC组初始给药方案下谷浓度均值（8.3±5.2） mg·L^-1明显低于肾功能正常组的谷浓度均值（14.3±8.4） mg·L^-1,有显著性差异（P=0.000）。ARC患者的初始给药方案谷浓度达标率为20.6%,肾功能正常组为40.1%,具有显著性差异（P=0.007）。ARC组万古霉素的临床总有效率和革兰阳性菌清除率分别为69.1%和67.6%,肾功能正常组为76.7%和81.6%,均无显著性差异（P=0.286;P=0.143）。结论：多数ARC患者初始方案万古霉素用药剂量不足,谷浓度达标率较肾功能正常患者更低。     

The relation between type of renal disease and renal drug clearance in children

Summary It is generally assumed that the renal clearance of drugs in patients with renal impairment are affected to a similar extent regardless of the type of renal disease (intact nephron hypothesis). We have studied the effect of underlying renal disease on the pharmacokinetics of cefotaxime and desacetylcefotaxime in two groups of children (ages 7 to 16 y) with varying degrees of renal dysfunction.Patients in group 1 (n=5) had intrinsic renal disease and those in group 2 (n=5) had extrinsic renal disease, as identified by the primary renal lesion. After a single intravenous dose of cefotaxime timed blood and urine samples were collected for 24 h; cefotaxime and desacetylcefotaxime were measured by HPLC.There were no significant differences between the groups in age, body surface area, urine output, creatinine clearance, total body clearance, nonrenal clearance, renal clearance, and volume of distribution at steady state of cefotaxime, and renal clearance of desacetylcefotaxime. However, the renal clearance: creatinine clearance (CL_R:CL_CR) ratios for both cefotaxime [1.34 in group 1 vs. 0.51 in group 2] and desacetylcefotaxime [1.58 in group 1 vs. 0.75 in group 2] were statistically significant between the two groups. Group 1 patients had an average CL_R:CL_CR ratio greater than 1 for both the parent compound and the metabolite, suggesting that net tubular secretion was still intact, despite a diminished glomerular filtration rate (CL_CR=24 ml·min^–1·1.73 m^–2). In contrast, patients in group 2 (CL_CR=49) ml·min^–1·1.73 m^–2) had an average CL_R:CL_CR ratio less than 1 for both cefotaxime and desacetylcefotaxime, suggesting that renal tubular transport mechanisms did not remain functional in these patients.Our findings suggest that the effect of renal insufficiency on the renal elimination of cefotaxime and its metabolite desacetylcefotaxime may depend on the cause of renal insufficiency.     

Pharmacokinetics and pharmacodynamics of lisinopril in advanced renal failure

To prevent drug accumulation and adverse effects the dose of hydrophilic angiotensin-converting enzyme (ACE) inhibitors, e. g. lisinopril, must be reduced in patients with renal failure. To obtain a rational basis for dose recommendations, we undertook a prospective clinical trial. After 15 days of lisinopril treatment pharmacokinetic and pharmacodynamic parameters were determined in patients with advanced renal failure (n=8; endogenous creatinine clearance [CL_CR]: 18 ml·min^?1·1.73m^?2) and in healthy subjects with normal renal function (n=16; CL_CR: 107 ml·min^?1·1.73m^?2). The volunteers received 10 mg lisinopril once daily, the daily dose in patients (1.1–2.2 mg) was adjusted to the individual CL_CR according to the method of Dettli [13]. After 15 days of lisinopril treatment the mean maximal serum concentration (C _max) in patients was lower than in volunteers (30.7 vs 40.7 ng·ml^?1, while the mean area under the concentration-time curve (AUC _{0–24 h}) was higher (525 vs 473 ng·h^?1·ml^?1). ACE activity on day 15 was almost completely inhibited in both groups. Plasma renin activity, angiotensin I and angiotensin II levels documented marked inhibition of converting enzyme in volunteers and patients. Furthermore, average mean arterial blood pressure in patients decreased by 5 mmHg and proteinuria from 3.9–2.7 g per 24 h after 15 days of treatment with the reduced dose of lisinopril. Adjustment of the dose of lisinopril prevents significant accumulation of the drug in patients with advanced renal failure during chronic therapy. Mean serum levels did not exceed this in subjects with normal renal function receiving a standard dose. Despite substantial dose reduction, blood pressure and proteinuria decreases were observed.     

肾功能亢进在重症患者中的发生率及对万古霉素应用的影响

目的： 研究肾功能亢进（ARC）在重症患者中的发生率和ARC对重症患者血清万古霉素浓度的影响。方法： （1）回顾性分析2016年1月-2017年6月某院重症医学科收治的所有检测过肾功能的患者，分析其ARC发生率。（2）回顾性分析2016年1月-2017年6月在该院重症医学科接受万古霉素常规剂量1 g q12h治疗的患者，评价ARC对血清万古霉素浓度的影响。结果： （1）本研究共纳入患者3 045名，研究结果表明重症患者ARC发生率为15.6%（474/3 045）。ARC组患者年龄显著低于非ARC组，肌酐清除率和GFR明显高于非ARC组。（2）本研究共纳入50例患者，ARC组的万古霉素稳态谷浓度显著低于非ARC组，谷浓度中位数分别为5.72（3.73，8.27）μg·mL^-1和14.06（8.74，22.14）μg·mL^-1，P<0.05。但2组之间的临床结局、微生物结局和死亡率没有显著差异。ARC组万古霉素稳态谷浓度低于10 μg·mL^-1的重症患者达78.9%，较非ARC组（29.0%）比例更高。万古霉素稳态谷浓度与年龄显著相关（ρ=0.739，P<0.05），与肌酐清除率显著相关（ρ=-0.716，P<0.05）。结论： 重症患者ARC发生率较高，ARC会使患者的万古霉素浓度难以达到治疗目标，这类患者需要根据肌酐清除率进行必要的给药剂量调整。     

Investigation of the role of organic cation transporter 2 (OCT2) in the renal transport of guanfacine,a selective α2A-adrenoreceptor agonist

Abstract

1.?Guanfacine is a selective α_2A-adrenoreceptor agonist primarily excreted as its unchanged form through urine in human. This study was to investigate the involvement of organic cation transporter 2 (OCT2) in the renal tubular secretion of guanfacine.

2.?Transport of guanfacine was characterized using human embryonic kidney (HEK293) cells expressing human OCT2 (hOCT2). The inhibitory effect of cimetidine on guanfacine uptake was also examined. In addition, in vivo pharmacokinetic study was conducted in rats to assess the effects of cimetidine on the pharmacokinetics of guanfacine.

3.?The accumulation of guanfacine in hOCT2-transfected HEK293 cells was both time- and concentration-dependent, and markedly higher than that in mock cells. The apparent K_m and V_max values of guanfacine uptake by hOCT2 were 96.19?±?7.49?μM and 13.03?±?0.49?nmol/mg protein/min, respectively. Guanfacine transport mediated by hOCT2 was significantly inhibited by a typical OCT2 inhibitor cimetidine with an IC₅₀ value of 93.82?±?1.13?μM. Co-administration of cimetidine significantly decreased the plasma clearance (CL_p) as well as the renal clearance (CL_r) of guanfacine in rats in a dose-dependent manner, resulting in a noticeable increase in the systemic exposure of guanfacine.

4.?These results indicated that OCT2 may be involved in the renal disposition of guanfacine.     

Population pharmacokinetics of rosuvastatin: implications of renal impairment,race, and dyslipidaemia

ABSTRACT

Objectives: To build the structural model of pharmacokinetics for rosuvastatin and evaluate the impact of demographic characteristics including renal function on its pharmacokinetic parameters.

Methods: A population pharmacokinetic analysis of rosuvastatin in healthy volunteers, subjects with dyslipidaemia, and renal failure patients was performed using non-linear mixed-effects modelling and a two-compartment pharmacokinetic model with simultaneous first- and zero-order absorption. Demographic covariates, dyslipidaemic state and renal function were evaluated for their impact on pharmacokinetic parameters by step-wise additions or deletions using the likelihood ratio test.

Results: Typical pharmacokinetic parameters were estimated for a healthy white male subject. For example, apparent oral clearance (CL/F?) was estimated to be 257?L/h. Age, smoking status, weight, body surface area, and lean body mass had no significant effect on rosuvastatin pharmacokinetics. The model predicted that CL/F for subjects with creatinine clearance (CLCR?) of 30?mL/min (moderate renal impairment) and of 50?mL/min (mild renal impairment) was 17% and 9.7% lower, respectively, relative to subjects with CLCR of 94?mL/min, the data set median value. CL/F was reduced by 71.1% and 43.7% in subjects with dyslipidaemia and in Asian subjects, respectively.

Conclusions: Reduction of CL/F of rosuvastatin is not considered clinically significant for patients with mild-to-moderate renal impairment. Rosuvastatin CL/F was reduced in subjects with dyslipidaemia, but it is important to realise that the safety/efficacy profile of rosuvastatin has been well established in this population. However, the potential for increased exposure in Asian subjects should be considered when initiating rosuvastatin treatment or increasing dose in this population.     

Comparison of intrinsic metabolic clearance in fresh and cryopreserved human hepatocytes

1. We compared the intrinsic clearance (CL_int) of a number of substrates in suspensions of fresh and cryopreserved human hepatocytes from seven donors.

2. CL_int values for a cocktail incubation of phenacetin, diclofenac, diazepam, bufuralol, midazolam, and hydroxycoumarin were 4.9?±?3.4, 18?±?7.2, 5.1?±?4.9, 6.3?±?3.3, 9.8?±?5.8 and 22?±?14?μl min^?1/10⁶ cells, respectively, and they correlated well with corresponding CL_int values using cryopreserved hepatocytes from 25 different donors.

3. CL_int values of each cocktail substrate and 20 AstraZeneca new chemical entities were compared in fresh and cryopreserved hepatocytes from the same three donors. There was a statistically significant correlation between CL_int in fresh and cryopreserved hepatocytes for each of the three livers (p?int values was 1.03.

4. In conclusion, the results add further support to the use of cryopreserved human hepatocytes as a screening model for the intrinsic clearance of new chemical entities.

     

肾功能亢进患者应用万古霉素致急性肾损伤的用药监护

目的 探讨肾功能亢进患者万古霉素个体化用药中出现急性肾损伤的原因。方法 对南京医科大学附属苏州医院使用万古霉素且发生急性肾损伤的3个病例进行药学监护,分析使用群体药动学软件预测万古霉素谷浓度准确性差的原因,寻找发生万古霉素急性肾损伤的原因。结果 在查明患者发生不良反应的原因后,对其进行针对性治疗,均获得较好的控制与转归。结论 肾功能亢进患者出现万古霉素相关性肾损害主要为联用肾毒性药物、肾脏灌注不足,临床用药中需加强用药监护,提高万古霉素用药安全性。     

Population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism—the Hokusai‐VTE phase 3 study

AimsThis study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep‐vein thrombosis and/or pulmonary embolism in the Hokusai‐VTE phase 3 study. The impact of the protocol‐specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL_cr) of 30 to 50 ml min^–1 or concomitant P‐glycoprotein inhibitor on edoxaban exposure was assessed using simulations.MethodsThe sparse data from Hokusai‐VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.ResultsA linear two‐compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non‐renal and renal. The latter increased non‐linearly with increasing CL_cr. Compared with healthy volunteers, inter‐compartmental clearance and the CL_cr covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co‐administration of P‐glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model‐based simulations revealed lower exposure in dose‐reduced compared with non‐dose‐reduced patients.ConclusionsThe adopted dose‐reduction strategy resulted in reduced exposure compared with non‐dose‐reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.     

202例次万古霉素血药浓度监测与临床应用分析

目的 分析万古霉素血药浓度监测结果及临床应用情况,为临床合理用药提供参考。方法 采用反相-高效液相色谱法测定万古霉素血药浓度,对万古霉素血药浓度监测结果及相关用药信息进行比较分析。结果 万古霉素谷浓度监测202次,平均血药谷浓度（14.36±8.12）mg/L,浓度小于10 mg/L的有68例次（33.66%）,在10～20 mg/L的有100例次（49.51%）,大于20 mg/L的有34例次（16.83%）;肾功能正常与异常组间,血药谷浓度有显著性差异;用药前后,各项肾功能指标无显著性差异。结论 万古霉素个体差异大,需加强血药浓度监测;针对肾功能异常患者,临床医生和药师需审慎评估给药剂量;临床医生应根据血药浓度及时调整用药方案,实现个体化给药。     

Use of a semi-physiological pharmacokinetic model to investigate the influence of itraconazole on tacrolimus absorption,distribution and metabolism in mice

1.?The aim of this study was to investigate the influence of itraconazole (ITCZ) on tacrolimus absorption, distribution and metabolism by developing a semi-physiological pharmacokinetic model of tacrolimus in mice.

2.?Mice were randomly divided into four groups, namely control group (CG, taking 3?mg kg^?1 tacrolimus only), low-dose group (LDG, taking tacrolimus with 12.5?mg kg^?1 ITCZ), medium-dose group (MDG, taking tacrolimus with 25?mg kg^?1 ITCZ) and high-dose group (HDG, taking tacrolimus with 50?mg kg^?1 ITCZ).

3.?Liver clearance (CL_li) decreased significantly (**p?<?0.01) in LDG (35.3%), MDG (45.2%) and HDG (58.7%) mice compared to CG mice. With respect to gut clearance (CL_gu), significant (**p?<?0.01) decrease was also revealed in LDG (35.9%), MDG (50.2%) and HDG (64.6%) mice. A significant (**p?<?0.01) higher tacrolimus brain-to-blood partition coefficient (K_t,br) was found in MDG (25.3%) and HDG (55.9%) mice than in CG mice. Moreover, a significant (*p?<?0.05) increase (16.3%) was found in the absorption rate constant (K_a) in HDG mice compared to CG mice. There was a significant (**p?<?0.01) association between ITCZ dose and the change in CL_gu (ΔCL_gu, r=??0.790), the change in CL_li (ΔCL_li, r=??0.787) and the change in K_t,br (ΔK_t,br, r?=?0.727), while the association between ITCZ dose and the change in K_a (ΔK_a) was not significant (p?>?0.05).

4.?These findings could be useful in predicting the efficacy and toxicity of tacrolimus, and drug–drug interaction of ITCZ and tarcolimus in human.     

Pharmacokinetic profiles of glycyrrhizin in patients with chronic hepatitis

The pharmacokinetics of glycyrrhizin (G) in eight patients with chronic hepatitis receiving chronically i.v. administration of 120 mg dose of G was investigated. The plasma concentration of G in the patients after dosing declined in a monophasic manner. However, the pharmacokinetic profiles varied among patients. The mean elimination half-life (t_1/2) and the total body clearance (CL_tot) were 6.0 h (range 4.3–10.7 h) and 7.9 ml h^?1 kg^?1 (4.5–12.7 ml h^?1 kg^?1), respectively. The variation of the CL_tot for G was closely related to that of aspartate aminotransferase (r = ?0.739, p <0.05) and alanine aminotransferase (r = ?0.783, p <0.05) activities in the plasma.     

Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function

Aims

The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy.

Methods

A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CL_cr) = 50–79 ml min⁻¹], moderate [CL_cr = 30–49 ml min⁻¹], severe [CL_cr <30 ml min⁻¹]).

Results

Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration–time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m⁻² day⁻¹, given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m⁻² day⁻¹ for patients with moderate renal impairment (suggested dose 1.9 mg m⁻² day⁻¹ for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m⁻² day⁻¹ in this cohort.

Conclusions

Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.     

Evaluation of “True” Creatinine Clearance in Rats Reveals Extensive Renal Secretion

The renal clearance of endogenous creatinine is widely used to assess glomerular filtration rate (GFR) and renal function in animal investigations. The objective of the present investigation was to evaluate the extent of renal secretion of endogenous creatinine in rats and the effect of probenecid, the classical inhibitor of organic anion transport, on creatinine clearance. Ten female Lewis rats received ³H-inulin (5-µCi i.v. bolus followed by 5 µCi/hr) throughout a 6-hr period. Three hours after initiation of the inulin infusion, probenecid was administered (92.4-mg/kg i.v. bolus followed by 0.59 mg/min/kg). Steady-state serum concentrations of about 500 µg/ml probenecid were achieved. Renal clearance was assessed between 1 and 3 hr (control) and between 4 and 6 hr (probenecid treatment). A preliminary study in seven rats demonstrated no time-dependent change in inulin or creatinine clearance between these two study intervals. Creatinine clearances were determined by an alkaline picrate assay which incorporated Fuller's earth (Lloyd reagent) to remove interfering noncreatinine chromogens from serum samples and these values were compared with those using a nonspecific picrate assay. True clearance ratios of creatinine to inulin (CL_cr/ CL_in) were greater than unity (2.33 ± 0.83, mean ± SD) and were significantly decreased after probenecid treatment (1.26 ± 0.28, P < 0.01). Probenecid had no effect on GFR, as assessed by inulin clearance. Using the nonspecific picrate assay, CL_cr/CL_in was 1.12 ± 0.41, which was not significantly different from unity and which decreased to 0.53 ± 0.12 after probenecid treatment. Therefore, creatinine undergoes extensive renal secretion in female Lewis rats.     

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     

Estimation of renal secretory function for organic cations by endogenous N1-methylnicotinamide in rats with experimental renal failure

To assess whether the secretory clearance of N ¹-methylnicotinamide (NMN), an endogenous organic cation, represents renal tubular secretion of the organic cation, the relationship between the secretory clearance of NMN, CL _scn(NMN),and that of tetraethylammonium bromide (TEA), CL _scn(TEA),was examined in normal and experimental renal failure (ERF) rats. TEA was selected as a representative organic cation secreted by the kidney. ERF was induced by glycerol, folate, salicylate, uranium, and gentamicin, substances which have been demonstrated to produce specific damage to the kidney by pathophysiological studies. Glomerular filtration rate (GFR), CL _scn(NMN),and CL _scn(TEA) decreased significantly in most of ERF rats, while blood urea nitrogen (BUN) increased significantly in all ERF rats. There was a statistically significant correlation (r=0.952, p<0.001) between the endogenous CL _scn(NMN) and CL _scn(TEA) in both the normal and ERF rats. Correlation analysis revealed that CL _scn(NMN) was superior to GFR in the degree of relationship to CL _scn(TEA),but BUN could not be used as an index for the secretion of NMN or TEA. Although the plasma concentration of NMN in most of the ERF rats was much higher than that in the normal rats, it affected neither the urinary clearance of NMN itself nor the excretion of TEA. From these findings, we propose that CL _scn(NMN) can be used as an index to assess renal tubular function for the secretion of organic cations that are excreted by both filtration and secretion without reabsorption.Abstracted in part from a dissertation submitted by Chang K. Shim to the Graduate School, Division of Pharmaceutical Sciences, University of Tokyo, in partial fulfilment of the Doctor of Philosophy degree requirements. This study was supported by a grant-in-aid for Scientific Research provided by the Ministry of Education, Science and Culture of Japan.