Performance of gentamicin population kinetic parameters in Portuguese neonates

Aim To evaluate the performance of eight different sets of gentamicin populational pharmacokinetic parameters, regarding potential implementation in clinical pharmacokinetic software as prior information. Methods The study involved 49 patients of 31.3±4.1 weeks of gestational age (GA), receiving gentamicin, and for whom peak and trough concentrations were obtained. Accuracy and precision were assessed by mean prediction error (ME), mean squared prediction error (MSE) and root mean squared prediction error (RMSE). Weighted prediction-error analysis was carried out in order to evaluate peak and trough concentrations together (ME_w, MSE_w and RMSE_w). Results The analysis showed CL=0.036 l/h/kg (<34 weeks GA) or CL=0.051 l/h/kg (≥34 weeks GA), and V _d =0.5 l/kg (≤37 weeks GA) or V _d =0.4 l/kg (>37 weeks of GA) as the most accurate and precise set of pharmacokinetic parameters (Set 4), presenting the highest percentage of clinically acceptable estimates (Error_Peak<1 μg/ml, and Error_Trough <0.375 μg/ml). Conclusion The adoption of the previously mentioned set of parameters as population estimates seems to be the best option, bearing in mind the obtained results. However, we strongly believe that pharmacokinetic parameter determination of gentamicin should be carried out whenever possible in order to improve the rationale and cost-effectiveness of therapy.     

Intravenous verapamil kinetics in rats: Marked arteriovenous concentration difference and comparison with humans

The pharmacokinetics of verapamil, a calcium channel blocker, were studied in male Sprague—Dawley rats following i.v. administration at a dose of 1 mg kg^?1. Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed-phase high-performance liquid chromatography. Verapamil was distributed to the extravascular tissues very rapidly as indicated by the large V_dss (2.99±0.57 1 kg^?1) and V_dβ (5.08 ± 0.541 kg^?1). The apparent terminal plasma T_1/2, MRT_iv, and CL_p were 1.59 ± 0.46, 1.26 ± 0.12 h, and 40.4 ± 9.73 ml min^?1 kg^?1, respectively. Marked arterial/venous differences were found with a considerable influence on the MRT and V_dss, and the terminal phase venous levels were higher than arterial levels by 103, 69, and 90%, respectively, for the three rats studied. The distribution of verapamil between plasma and erythrocytes occurred very rapidly and was identical in vitro and in vivo. The average blood to plasma and plasma to blood cell concentration ratios were 0.85 and 1.47, respectively. In contrast to propranolol, blood data rather than plasma data should be used to predict the hepatic extraction ratio of verapamil (0.87). The plasma protein binding of verapamil in humans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic parameters between rats and humans is presented and the potential shortcomings of using T_1/2 or CL_p and the advantage of using CL_u (unbound plasma clearance) in interspecies scaling is also discussed.     

HPLC-MS/MS法测定血浆中十肽化合物LXT-101及Beagle犬药代动力学研究

建立HPLC-MS/MS法测定血浆中十肽化合物(LXT-101)的浓度，并应用于Beagle犬的药代动力学研究。血浆样品采用乙腈直接沉淀蛋白的方法，内标(IS)选用¹²⁷I-LXT-101，采用ESI-MS/MS二极质谱，选择反应监测(SRM)方式进行检测。LXT-101的线性范围为0.5～500.0 ng·mL^-1(r²>0.993 0)，绝对回收率为85.2%～90.7%，日内、日间精密度(RSD%)均小于10.9%，准确度(RE)在±1.8%之内。血浆中的最低检测限(LOQ)为0.5 ng·mL^-1。该法操作简便、快速、灵敏度高。可检测出低剂量肌注(im)给药后犬体内的血药浓度，适于临床前药代动力学研究。     

Pharmacokinetics of isoforskolin after administration via different routes in guinea pigs

1.?The objective of this study was to characterize the pharmacokinetics of isoforskolin after oral, intraperitoneal and intravenous administration, as well as to compare bioavailability.

2.?Isoforskolin was administered to guinea pigs at a dose of 2?mg/kg. Plasma concentrations were determined by high-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (HPLC–ESI–MS/MS) method. The pharmacokinetic parameters were calculated by a noncompartmental method. A compartment model was also adopted to describe the pharmacokinetic profiles.

3.?The pharmacokinetic behavior of intravenously administered isoforskolin was characterized by rapid and extensive distribution (V_z?=?16.82?±?8.42?L/kg) followed by rapid elimination from the body (Cl?=?9.63?±?4.21?L/kg/h). After intraperitoneal administration, isoforskolin was absorbed rapidly (T_max?=?0.12?±?0.05?h). The pharmacokinetic profiles of isoforskolin were similar after intraperitoneal and intravenous administration, except for the concentrations at the initial sampling times. Isoforskolin was also absorbed rapidly following oral dosing; however, the concentration–time data were best fit to a one-compartment model, which was different from that observed after intravenous and intraperitoneal administration. Following intraperitoneal and oral administration, the absolute bioavailability of isoforskolin was 64.12% and 49.25%, respectively.

4.?Isoforskolin is a good candidate for oral administration because of its good oral bioavailability.     

Effect of ferulic acid on the brain pharmacokinetics of tetramethylpyrazine in conscious rats

1.?In traditional Chinese medicine, Angelica sinensis is often coprescribed with Ligusticum chuanxiong Hort for the treatment of ischemic cerebrovascular diseases. Tetramethylpyrazine (TMP) is one of the most important active ingredients isolated from Ligusticum chuanxiong Hort; ferulic acid (FA) is the main water-soluble component of Angelica sinensis.

2.?The purpose of this study is to investigate the possible effect of FA on the brain pharmacokinetics of TMP in conscious Sprague-Dawley rats. The pharmacokinetic parameters of TMP were investigated in brain microdialysates after oral and intravenous administration of TMP (4?mg/kg) to rats in the absence and presence of FA (5?mg/kg). Samples were collected at timed intervals for the measurement of TMP by a rapid and sensitive UPLC-MS/MS method.

3.?The pharmacokinetic parameters were calculated by noncompartmental analysis for brain microdialysates. The brain pharmacokinetic data for TMP showed significant increases in C_max, t_1/2, AUC_0–inf and MRT_0–inf after combination with FA. After intragastric administration with FA, there were significant decreases in the T_max (from 38.33?±?5.77 to 21?±?5.48?min; p?0.01) of TMP. This study indicated that potential drug–drug interaction between TMP and FA should be taken into consideration and the combined administration is beneficial in improving the bioavailability of TMP in the brain.     

栀子-闹羊花配伍对大鼠血浆中闹羊花毒素Ⅱ和闹羊花毒素Ⅲ的药动学影响

目的考察栀子与闹羊花配伍对闹羊花中闹羊花毒素Ⅱ和闹羊花毒素Ⅲ药动学的影响。方法建立LC-MS/MS测定大鼠血浆中闹羊花毒素Ⅱ和闹羊花毒素Ⅲ的分析方法,并用此方法测定大鼠口服给予闹羊花与栀子配伍液及闹羊花单煎液后大鼠体内的闹羊花毒素Ⅱ和闹羊花毒素Ⅲ的血药浓度,计算其药动学参数并统计分析。结果闹羊花毒素Ⅱ在1～200 ng·mL^–1、闹羊花毒素Ⅲ在1～100 ng·mL^–1内线性关系良好(r>0.999),质控样本精密度均<12%,准确度RSD<20%。栀子配伍闹羊花给药和单独给药后体内闹羊花毒素Ⅱ的AUC_0–t分别为(260.44±51.67)和(213.39±59.03) h·ng·mL^–1,闹羊花毒素Ⅲ的AUC_0–t分别为(60.97±22.78)和(22.38±5.55)h·ng·mL^–1。与闹羊花单煎给药相比,栀子与闹羊花配伍给药后闹羊花毒素Ⅱ的T_1/2和MRT₍(0–t))显著升高,闹羊...     

Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours

1.?The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents.

2.?Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24?h. Etoposide plasma concentration-time data was modelled using NONMEM^® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V_d) were determined by a nonlinear mixed effect model.

3.?The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V_d). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70?kg) values of CL and V_d were 2.31?L/hr and 17.5?L, respectively. The CL and V_d allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters.

4.?The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V_d increased with increasing weight similar to BSA.     

A comparison of HPLC and bioassay methods for plasma melanotan-II (MT-II) determination: Application to a pharmacokinetic study in rats

The pharmacokinetic profile of the melanotropic peptide, melanotan-II (MT-II), was determined in rats following a 0.3 mg kg^?1 intravenous dose. Regression analysis of the plasma MT-II concentrations determined using HPLC and bioassay methods indicated the existence of a significant linear correlation (r = 0.90, p < 0.001). The plasma concentration versus time plots determined using the two assay methods yielded biphasic disposition profiles that were essentially superimposable. The following pharmacokinetic parameters were assessed from plasma concentration versus time data using both methods: C_max, AUC, CL_s, t_1/2β, MRT V_dβ, and V_ss. Statistical comparison showed that the parameters measured by each method were not significantly different (at the 0.05 level) except for t_1/2β, MRT and V_ss. The presence of even one aberrant data point in the β-phase can significantly influence t_1/2β when only a few data points are available in the β-phase. Since MRT and V_ss were calculated from t_1/2β it is not surprising that these two parameters also differed between methods.     

HPLC determination and pharmacokinetics of the new original domestic drug dibufelon®

A simple, specific, sensitive, and precise high-performance liquid chromatography (HPLC) assay with UV detection has been developed for quantitative determination of fenozan acid in human blood plasma. Using this method, the pharmacokinetics of the new domestic preparation dibufelon (OOO Consortium-PIK, Russia) were investigated after a single peroral administration of an 800-mg dose in 12 healthy volunteers. It is established that the drug is rapidly absorbed from the GI tract into the systemic blood flow [C _max ,178 ± 29 ng/mL; T _max, 3.9 ± 0.5 h; AUC _0–∞, 1434 ± 269 (ng ∙ h)/mL; C _max/AUC _0–∞, 0.135 ± 0.011 L/h], rather well retained in humans (MRT, 8.6 ± 0.8 h; T ₁/₂, 5.3 ± 0.8 h), and, despite a rapid total clearance (Cl _t ,824 ± 167 L/h), penetrates well into organs and tissues (V _Z , 5590 ± 1204 L).     

Importance of Within Subject Variation in Levodopa Pharmacokinetics: A 4Year Cohort Study in Parkinson’s Disease

The purpose of the study was to describe the population pharmacokinetics of levodopa in patients with Parkinson’s disease studied in 5 trials (10 occasions) over 4 years. Twenty previously untreated Parkinsonian patients were investigated. Each trial consisted of a 2-hr IV infusion of levodopa (1 mg/kg/h) with concomitant oral carbidopa given on two occasions separated by 72hr with no levodopa in between. This trial design was repeated at 6, 12, 24 and 48 months. A two-compartment pharmacokinetic model with central volume (V₁), peripheral volume (V₂), clearance (CL) and inter-compartmental clearance (CL_ic) was used to fit plasma levodopa concentrations. The model accounted for levodopa dosing prior to each trial and endogenous levodopa synthesis. Population parameter estimates (geometric mean) and population parameter variability (PPV; SD of normal distribution) were V₁ 11.4 l/70 kg (0.44), CL 30.9 l/h/70 kg (0.25), V₂ 27.3 l/70 kg (0.27), and CL_ic 34.6 l/h/70 kg (0.48). PPV was partitioned into between subject variability (BSV) which was 0.12 V₁, 0.13 CL, 0.15 V₂, 0.28 CL_ic, within trial variability (WTV) which was 0.16 V₁, 0.13 CL, 0.08 V₂, 0.18 CL_ic and between trial variability (BTV) which was 0.40 V₁, 0.17 CL, 0.21 V₂, 0.34 CL_ic. Neither structural nor random levodopa pharmacokinetic parameters were associated with the time course of development of fluctuation in motor response. Variability in levodopa pharmacokinetic parameters (particularly V₁) may result in variability in plasma levodopa concentrations that could contribute to fluctuations in motor response.     

氢化阿托酸在大鼠体内立体选择性时间药代动力学

以余弦法分析氢化阿托酸(HTA)药代动力学参数证明,下列参数具有昼夜节律:标准明暗周期下,S(+)-HTA的T_1/2β和CL,R(-)-HTA的T_1/2β以及外消旋体的CL和MRT;反相明暗周期下,S(+)-HTA的T_1/2β和AUC,R(-)-体的CL以及外消旋体的CL。下列参数具有立体选择昼夜节律:标准明暗周期下,S(+)-HTA的CL,反相明暗周期下,S(+)-HTA的T_1/2β和AUC以及R(-)-HTA的CL。以外消旋体给药后,大鼠体内由R(-)-体向S(+)-体的转化过程,可出现昼夜节律,在两种明暗周期下,峰值相位均位于黑暗期之末,据此,提出HTA的清晨给药治疗方案。     

Changes in urinary PGE<Subscript>2</Subscript> after ibuprofen treatment in preterm infants with patent ductus arteriosus

Purpose  To investigate changes in urinary PGE₂ after ibuprofen treatment in preterm infants with patent ductus arteriosus (PDA). Methods  Twenty preterm infants with a hemodynamically significant PDA (gestational age, 28.6 ± 2.3 weeks) and 20 controls (gestational age, 30.4 ± 1.5 weeks) were prospectively enrolled at 48–72 h of life. After enrollment, the former underwent conventional ibuprofen-lysine treatment. At 48–72 h (T₀) and 108–144 h of life (T₁), urine samples were noninvasively collected in both groups to measure urinary PGE₂ concentrations (enzyme immunoassay method), and renal function was investigated. Results  Urinary PGE₂ decreased significantly both in ibuprofen-treated patients (66.95 ± 16.78 vs. 27.15 ± 17.92 pg/mL, P < 0.001) and in controls (71.7 ± 16.2 vs. 53.2 ± 18.4 pg/mL, P < 0.001) from T₀ to T₁. However, urinary PGE₂ at T₁ was significantly lower (P < 0.001) in the ibuprofen group compared to the control group. Acute renal failure occurred in three ibuprofen-treated patients (15%). Conclusions  Ibuprofen markedly reduces (59.4%) urinary PGE₂ and may alter renal function in the newborn.     

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects

Objective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg^–1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4–5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (V_ss) 673 l; volume corrected by real body weight (V_ss · kg^–1) 11.2 l ·  kg^–1; total clearance (CL) 51.6 h^–1; and terminal half-life (t_1/2) 10.3 h. The V_ss (898 l) and CL (71.6 l · h^–1) were significantly higher in obese patients. But V_ss · kg^–1 (9.4 l · kg^–1) and t_1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15–18 l · h^–1) and the t_1/2 prolonged (32–34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant. Received: 22 December 1995 / Accepted in revised form: 5 June 1996     

The Pharmacokinetics and Absorption of Recombinant Human Relaxin in Nonpregnant Rabbits and Rhesus Monkeys After Intravenous and Intravaginal Administration

Recombinant human relaxin (rhRlx) is being developed as a potential cervical ripening agent to be applied intravaginally or intracervically prior to parturition. The pharmacokinetics and absorption of rhRlx were determined in nonpregnant female rabbits and rhesus monkeys after intravenous bolus (iv) and intravaginal administration of 0.1 mg/kg; additionally, rabbits were dosed with 0.5 mg/kg intravaginally. In rabbits (n = 6), mean (±SD) peak concentrations following iv bolus administration were 1554 ± 296 ng/mL. The weight-normalized clearance (CL/W) was 5.9 ± 0.4 mL/min/kg, initial volume of distribution (V ₁/W) was 57 ± 9 mL/kg, and volume of distribution at steady state (V _SS/W), assuming central compartment elimination, was 240 ± 20 mL/kg. V _ss/W could be as large as 2000 ± 400 mL/kg without this assumption. The estimated amounts of rhRlx absorbed in rabbits following intravaginal administration of 0.1 and 0.5 mg/kg (n = 5/dose) were 3.1 ± 1.4 and 0.7 ± 0.3%, respectively; peak concentrations were 600 ± 297 and 1066 ± 584 pg/mL, respectively. In rhesus monkeys (n = 5) after iv administration, peak concentrations were 971 ± 277 ng/mL; CL/W was 4.1 ± 0.6 mL/ min/kg, V ₁/W was 78 ± 25 mL/kg, and V _ss/W, assuming central compartment elimination, was 690 ± 220 mL/kg. The upper limit for V _ss/W was 1600 ± 200 mL/kg when no assumptions were made regarding site (compartment) of elimination. After intravaginal administration (n = 6), two monkeys had undetectable rhRlx concentrations throughout the 48-hr sampling interval; one monkey had only one sample containing measurable rhRlx (51 pg/mL) at 24 hr; and three monkeys absorbed <2% of the 0.1 mg/kg dose. Peak concentrations in these three animals ranged from 64 to 1475 pg/mL. The absorption of rhRlx was low and variable in both species, and similar results have been observed in women.     

非诺贝特双层渗透泵片在Beagle犬体内的药动学研究

目的 研究非诺贝特双层渗透泵片在犬体内的药动学特征,并评价受试制剂和参比制剂的生物等效性。方法 采用LC-MS测定比格犬体内的血药浓度,采用DAS 2.1.1软件计算药动学参数。结果 受试制剂和参比制剂血浆中非诺贝特酸的C_max分别为（1 100.0±771.2）、（924.3±564.0）ng/mL,t_max分别为（6.7±8.5)、（2.5±0.5）h,AUC0-t分别为（17 841.1±12 220.7）、（17 615.5±12 870.2）ng·h/mL;t_1/2分别为（17.7±8.2）、（16.4±3.3）h,MRT_0-t分别为（24.7±4.0）、（24.5±5.2）h,受试制剂中非诺贝特酸的平均相对生物利用度为（104.7±12.4）%。结论 受试制剂非诺贝特渗透泵片和参比制剂非诺贝特缓释胶囊具有生物等效性。     

咪达唑仑片在中国维吾尔族和汉族健康人体的药动学比较

目的研究健康维吾尔族和汉族志愿者单剂量口服咪达唑仑片的药动学。方法维吾尔族、汉族健康志愿者各10名,男、女各半,单剂量口服15 mg咪达唑仑片后,用HPLC法测定咪达唑仑的血浆浓度,运用DAS 2.0程序以非室模型拟合药动学参数,并对药动学参数进行独立样本t检验和非参数Mann-Whitney U test检验,以判断药动学是否存在显著性的民族差异。结果单剂量口服15 mg咪达唑仑片后,维吾尔族志愿者的主要药动学参数分别为:ρmax(124.8±50.0)μg.L-1,tmax(0.8±0.5)h,t1/2z(1.9±0.7)h,MRT0-12 h(2.8±0.8)h,CL/F(0.9±0.4)L.h-1.kg-1,Vz/F(2.3±0.7)L.kg-1和AUC0-12 h(343.2±150.9)μg.h.L-1。汉族健康受试者的主要药动学参数分别为:ρmax(103.1±26.4)μg.L-1,tmax(1.5±0.7)h,t1/2z(3.0±0.8)h,MRT0-12 h(3.6±0.4)h,CL/F(0.7±0.2)L.h-.1kg-1,Vz/F(2.7±0.8)L.kg-1和AUC0-12 h(368.8±103.4)μg.h.L-1。经检验,维吾尔族的tmax、t1/2z和MRT0-12 h比汉族的短,差异有显著性统计学意义,其余参数的民族差异无显著性统计学意义。两个民族的部分受试者的药-时曲线有双峰。结论单剂量口服咪达唑仑片后,汉族和维吾尔族健康志愿者的药动学存在较大的个体差异,且消除速率的民族差异有显著性统计学意义,临床应用时应注意个体化给药。     

Prediction of the Distribution Volumes of Cefazolin and Tobramycin in Obese Children Based on Physiological Pharmacokinetic Concepts

So as to estimate the appropriate dose of antibacterial drugs in obese children, prediction of the volume of distribution in these children was attempted based on physiological pharmacokinetic concepts which had been constructed from results in normal-weight children. Serum concentration–time data after intravenous drip infusions of tobramycin and cefazolin were analyzed using noncompartmental analysis of obese children in whom the degree of obesity ranged from 30 to 80%. Volume of distribution at steady state (V _ss) per total body weight of tobramycin was significantly less than that for normal-weight children (P < 0.05), whereas the value of cefazolin was almost equal to that for normal-weight children. The equation to express the difference of V_ss between cefazolin and tobramycin obtained in normal-weight children failed in obese children, suggesting that there is a large decrease in the extracellular space in obese children exceeding the interindividual variations in normal-weight children. The V _ss value (liter) for tobramycin was predicted by using the equation 0.261 · {ideal body weight (kg) + 0.4 · [total body weight (kg) – ideal body weight (kg)]}. The V _ss value of cefazolin was predicted to be 0.3 · (predicted V _ss of tobramycin) + 0.052 · total body weight (kg). A good correlation between the predicted and the observed V _ss values was obtained.     

Pharmacokinetics of Liquiritigenin in Mice,Rats, Rabbits,and Dogs,and Animal Scale-Up

Pharmacokinetics of liquiritigenin (LQ) and its two glucuronide metabolites, M1 and M2, in mice, rats, rabbits, and dogs and animal scale-up of the pharmacokinetic parameters of LQ were evaluated. After intravenous administration of LQ, the AUC (AUC_0?t) values of LQ, M1, and M2 were proportional to LQ doses in all animals studied. Animal scale-up of some pharmacokinetic parameters of LQ was performed based on the parameters after its intravenous administration (20 mg/kg; in the linear pharmacokinetic range) to the four species. Linear relationships were obtained (r > 0.968) between log CL (or CL/f_u) (L/h) and log species body weight (W) (kg) [CL (or CL/f_u) = 3.29 (34.0) W^{0.723 (0.789)}] and log V_ss (or V_ss/f_u) (L) and log W (kg) [V_ss (or V_ss/f_u) = 0.340 (3.52) W^{0.882 (0.948)}]. Interspecies scale-up of plasma concentration–time data of LQ using apolysichron (complex Dedrick plots) resulted in similar profiles, and plasma concentration–time profile of humans were predicted using the well-fitted four animal data. Our results indicate that the LQ data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters of LQ in humans. These parameters can serve as guidelines for better planning of clinical studies. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4327–4342, 2009     

A study of factors which determine the pharmacological response to vitamin K in coumarin anticoagulated rabbits

The pharmacological response to vitamin K has been determined by measuring prothrombin complex activity (P.C.A.) in male New Zealand White rabbits anticoagulated (P.C.A. <20%) with the long acting 4-hydroxycoumarin brodifacoum, at a dose (10 mg/kg) which produces maximum antagonism of vitamin K₁. Thus, according concurrent concepts, this animal model may be used to assess vitamin K requirements in the absence of a functional vitamin K-epoxide reductase. After intravenous administration of vitamin K₁ (1 mg/kg) P.C.A. reached a maximum (64±19%) at 3 hr and then declined at a rate which corresponds to complete inhibition of clotting factor synthesis. Vitamin K₂ (1 mg/kg) stimulated clotting factor synthesis for 2 hr, while cis-vitamin K₁, vitamin K₃, vitamin K₁ 2,3-epoxide and oral administration of vitamin K₁ were ineffective. Plasma concentrations of vitamin K₁ fell steeply during the 12 hr following administration of a pharmacological dose, and then declined with a terminal half-life of 18.9 ± 9.0 hr. Comparison of the phamacodynamic and pharmacokinetic data indicated that plasma concentrations in the range 0.4–1.0 μg/ml are required for clotting factor synthesis in the limiting situation of maximum antagonism of vitamin K by coumarin anticoagulants. These findings explain why frequent and repeated administration of vitamin K₁ may be necessary during coumarin poisoning.     

Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone

Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d₉-methadone.The pharmacokinetic profiles of d₉-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d₉-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD₅₀ value for a single intravenous dose of d₉-methadone was 2.1-fold higher than that for methadone. Moreover, d₉-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy.