Influence of renal failure,rheumatoid arthritis and old age on the pharmacokinetics of diflunisal

Summary The single-dose plasma kinetics of diflunisal was studied in healthy young and old subjects, in patients with rheumatoid arthritis, and in patients with renal failure. The plasma and urine kinetics of the glucuronidated metabolites of diflunisal were studied in the healthy elderly subjects and in the patients with renal failure. In addition, the multiple-dose plasma kinetics of diflunisal was assessed in healthy volunteers and in patients with rheumatoid arthritis. After a single dose of diflunisal the terminal plasma half-life, mean residence time and apparent volume of distribution were higher in elderly subjects than in young adults. No difference was observed in any pharmacokinetic parameter between age-matched healthy subjects and patients with rheumatoid arthritis. The elimination half-life of unchanged diflunisal was correlated with the creatinine clearance (r=+0.89) and its apparent total body clearance exhibited linear dependence on creatinine clearance (r=+0.78). In patients with renal failure, the terminal plasma half-life and mean residence time of diflunisal were prolonged. The renal and apparent total body clearances were lower, the mean apparent volume of distribution was higher and the mean area under the concentration-time curve extrapolated to infinity (AUC) was greater in the renal failure patients than in controls. The plasma concentration of the glucuronidated metabolites rapidly rose to levels above those of unchanged drug in renal patients, whereas they were lower than those of unchanged diflunisal in controls. The AUC (0–96 h) of diflunisal glucuronides in the patients was four-times that in controls, and the terminal elimination half-life of the glucuronides was prolonged in them. The renal excretion and clearance of diflunisal glucuronides were reduced when renal function was impaired. After multiple dosing, the pre-dose steady-state plasma-concentration increased with decreasing creatinine clearance (r=-0.79). When the plasma concentration exceeded 200 μmol·1⁻¹, the elimination half-life was doubled, due to partial saturation of diflunisal conjugation. This finding suggests that lower doses could be used in long-term treatment. Thus, old age and arthritic disease appear to have little influence on the kinetics of diflunisal in the absence of renal functional impairment. Ordinary doses can be given for short term treatment of elderly patients with or without RA. In patients with renal failure, however, reduced doses of diflunisal are recommended.     

Comparison of bioavailability and pharmacokinetics of diclofenac sodium and diclofenac potassium in normal and dehydrated rabbits

Two different salts of diclofenac, diclofenac sodium and diclofenac potassium, in tablet dosage form were tested for their bioavailability and disposition kinetics in a group of eighteen rabbits in normal and experimentally induced dehydrated conditions with a wash out period of 7 days between both stages of study.  Biochemical and physiological parameters were also measured in both normal and dehydrated states.  Diclofenac levels in plasma were determined using a validated reversed phase HPLC method.  Primary kinetic parameters i.e.  AUC_0－¥, C_max, T_max and other disposition kinetics were obtained with non-compartmental procedure.  Biochemical parameters i.e. packed cell volume, plasma glucose and total lipid concentration in dehydrated rabbits increased significantly.  Plasma concentration of diclofenac sodium and diclofenac potassium decreased significantly in water deprived rabbits.  In comparison, diclofenac potassium in normal and dehydrated state of the same group of rabbits showed a significantly increased plasma concentration when compared with diclofenac sodium.     

LC-MS/MS法测定人血浆中西酞普兰及其在制剂生物等效性中的应用

A sensitive and selective LC-MS/MS method for determination of citalopram in human plasma was established to study the bioequivalence of different formulations containing citalopram. The samples were simply pretreated by protein precipitation using acetonitrile, and then analyzed on a Zorbax Extend C₈column. The mobile phase consisted of acetonitrile-water-formic acid (60∶40∶0.2), at a flow-rate of 0.5 mL·min^-1. A Thermo Finnigan TSQ Quantum Ultra tandem mass spectrometer equipped with electrospray ionization source was used as detector and was operated in the positive ion mode. Selected reaction monitoring using the precursor to product ion combinations of m/z325 → m/z109 and m/z265 → m/z167 was performed to quantify citalopram and the internal standard, respectively. The pharmacokinetic parameters of citalopram in different formulations were calculated by non-compartment model. The linear calibration curves were obtained in the concentration range of 0.10-100 μg·L^-1. The lower limit of quantification was 0.10 μg·L^-1. The intra- and inter-day relative standard deviation (RSD) over the entire concentration range was less than 5.2%. Accuracy determined at three concentrations (0.25, 8.00 and 90.0 μg·L^-1 for citalopram) ranged from -4.7% to 1.3%. Each plasma sample was chromatographed within 3.0 min. The method was successfully used in bioequivalence study of citalopram in human plasma after oral administration of 20 mg citalopram. Calculated with AUC_{1-120 h}, the bioavailability of two formulations was (102.1±10.9)%. The method is rapid, selective, robust and is proved to be suitable for bioequivalence evaluation of different formulations containing citalopram.     

Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder

Rationale: Search for alternatives to lithium therapy for mood disorders commenced with anticonvulsants, carbamazepine (CBZ) and valproic acid (VPA), in the late 1970s. The comparative safety and efficacy data of CBZ and VPA monotherapy in patients with bipolar disorder remain to be established. Objectives: The main objectives of the study were to assess the relative anti-manic efficacy and safety of CBZ and VPA; to study the feasibility of using either, as a first line anti-manic agent; to investigate and generate clinically relevant parameters involving therapeutic drug monitoring of the two drugs. Methods: After a 2-day screening period, suitable patients (n=30) were randomly assigned to treatment with CBZ or VPA. Both the drugs were started with an average dose of approximately 20 mg/kg body weight per day. Further increment in dose was carried out at weekly intervals, guided by clinical improvement, serum levels and treatment emergent adverse events. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. A favourable clinical response was defined a priori as a decrease of more than 50% from baseline in Young Mania Rating Scale total score. Results: Both CBZ and VPA were found to be efficacious as single first-line anti-manic agents, however VPA proved to be better. Using the intent-to-treat analysis, the VPA group showed a significant fall in YMRS total scores after week 1 while the CBZ group showed a significant fall after week 2. In the primary efficacy analysis, valproate group experienced significantly greater mean improvement in Young Mania Rating Scale total score than the CBZ group. Of the VPA treated patients, 73% showed a favourable clinical response while 53% of the patients on CBZ responded favourably. In the CBZ group, significantly more patients received rescue medication during the week 2 and the requirement was quantitatively more as compared to the VPA group. The steady state serum concentration (Css) of CBZ ranged from 3 to 9 μg/ml; however, it did not appear to correlate with the dose or clinical response. The Css of VPA ranged from 50 to 100 μg/ml; a linear correlation was found between the dose and serum levels of VPA as well as between weekly rise in serum levels and clinical response. Weekly dose escalations of VPA also correlated positively with corresponding rise in serum levels. Significantly more patients in the CBZ group reported adverse events, including nausea, vomiting and dizziness, than VPA. Conclusions: The findings from this study suggest that both CBZ and VPA monotherapy is feasible for treatment of acute mania; however, VPA is more efficacious in terms of its early onset of action, lesser requirement for rescue medication and better tolerability. Further work needs to be undertaken to characterise the manic patients in terms of their differential psychopharmacologic response profile. Received: 9 July 1999 / Accepted: 11 January 2000     

Monocyte and neutrophil direct counts correlate with C-reactive protein plasma concentration in patients with acute pancreatitis

Acute pancreatitis (AP) is associated with the intensive inflammatory response in white blood cells (WBC) and C-reactive protein (CRP). This paper presents the relationship between the CRP plasma concentration and the direct counts of peripheral WBC in AP during the initial five days. The study consisted of 56 patients with AP, 36 patients with mild form of AP and 20 patients with severe form of AP. ABX VegaRetic hematological analyzer was used to perform the count of blood cells, and the immunonephelometric method was performed to measure the CRP concentration levels. AP patients presented with WBC count values in the range of 3.2 − 22.4 × 10³/μl and CRP concentration levels in the range 3.3 − 599.8 mg/l. The WBC count correlates with CRP levels during the entire observation period. The relationship of CRP and WBC is expressed in the following regression equation: WBC (10³/μl) = 3.66 + 1.40 × log_eCRP (mg/l). The highest median neutrophil count (8.15 × 10³/μl) was observed on the first day. The count decreased to 5.27 × 10³/μl on the fifth day. The most substantial finding in this study involved the values found for the monocytes and CRP (r= 0.53; p<0.001). Day two and day three were the highest (r=0.59, p<0.001). On day two, the regression equation for this relationship is: Monocytes (10³/μl) = −0.34 + 0.21 × log_eCRP(mg/l). The correlation between direct monocyte count and plasma CRP concentration in AP reflect a CRP-dependent stimulation of IL-6 release from activated blood monocytes.     

Distribution and elimination of hydroflumethiazide in man

Summary The pharmacokinetics of hydroflumethiazide (HFT) were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion, HFT behaved according to a three-compartment model. Two distribution phases were observed, with mean half-lives of 0.26 and 0.85 h, reflecting distribution to red blood cells and tissues. Mean biological half-life (t_1/2β ) after infusion was 5.2 h. Renal blood and plasma clearance of HFT, as well as the ratio renal blood clearance/renal plasma clearance of HFT, were lower after infusion than during the infusion, due to the distribution characteristics of HFT. After a single oral dose of 2 μmol/kg, t_1/2β was significantly shorter in all subjects than after a single oral dose of 6 μmol/kg, with mean t_1/2β of 8.7 and 17.9 h, respectively. Due to lack of a sufficiently sensitive method for determination of HFT in plasma, it could not be established whether the observed dose-dependent difference in biological half-life of HFT was caused by variation in renal clearance and/or the volume of distribution.     

Plasma levels of aspirin following effervescent and enteric coated tablets,and their effect on platelet function

Summary Oxcarbazepine (oxcarb) 600 and 900 mg (2360 and 3540 μmol) was taken by 3 volunteers (2 ♀, 1 ♂; 45–67 kg; age 22–34 years) after an overnight fast. Blood, saliva and urine were collected for the next 72 h for assay of oxcarb, 10,11-dihydro-10-hydroxy-carbamazepine (OHcarb), and 10,11-dihydrotrans-10,11-dihydroxy-carbamazepine (diol). Oxcarb reached a maximum level of about 1 μg/ml (3.93 μmol/l) within 1 h and dropped below the detection limit (0.1 μg/ml=0.39 μmol/l) within 3 h. The active metabolite OHcarb appeared in the blood before oxcarb and reached the higher maximum level of 7.4 μg/ml (29 μmol/l) after 7 h. Thereafter serum levels decreased with a t_1/2 of about 25 h, and after 40 h with a t_1/2 of 9 h, the latter agreeing with the renal excretory t_1/2 calculated from the urine data (10 h). The ratio of OHcarb concentration in saliva to that in plasma varied considerably (0.3–1.7; median 1; r>0.9), whereas that of blood to plasma was 1.25 with only small variation (r>0.98); OHcarb concentrations in erythrocytes were 50% higher than in plasma. Diol was detected in blood (maximum level 0.5 μg/ml=1.84 μmol/l) in 2 volunteers. 45% of the dose could be recovered in urine (Oxcarb 5%, OH-carb 36%, Diol 4%). Whereas Oxcarb was completely conjugated, only 25% of OHcarb was conjugated and diol was unconjugated.     

Endothelium-derived hyperpolarizing factor, but not nitric oxide or prostacyclin release, is resistant to menadione-induced oxidative stress in the bovine coronary artery

The interaction of superoxide anions (O₂ ^–) generated by menadione with the synthesis and/or action of nitric oxide (NO), prostacyclin (PGI₂) and endothelium-derived hyperpolarizing factor (EDHF) was investigated in segments of the left anterior descending coronary artery (LAD) isolated from bovine hearts. EDHF and NO release were monitored by superfusion bioassay in segments pre-constricted with the thromboxane mimetic, U46619, PGI₂ release in addition by enzyme immunoassay for 6-keto-prostaglandin F_1α, and generation of O₂ ^– by lucigenin-enhanced chemiluminescence. Bradykinin (1–1,000 pmol) elicited a prominent, endothelium-dependent, relaxant response, 50–60% of which was insensitive to combined blockade of cyclooxygenase with diclofenac (1 μM) and NO synthase with N ^G-nitro-l-arginine (50 μM). This diclofenac/N ^G-nitro-l-arginine-insensitive relaxant response was completely abrogated in the presence of tetrabutylammonium (3 mM), a non-selective inhibitor of Ca²⁺-dependent K⁺ channels, or when the segments were pre-constricted with potassium chloride (60 mM) instead of U46619, and thus most likely mediated by EDHF. Despite causing a two- to fourfold increase in the concentration of O₂ ^– in or at the vessel wall, menadione (30 μM) did not affect the diclofenac/N ^G-nitro-l-arginine-insensitive relaxant response to bradykinin. When administered in the absence of N ^G-nitro-l-arginine, however, menadione significantly inhibited the relaxant response to bradykinin, presumably by attenuating the NO-mediated relaxation. Menadione also abolished the bradykinin-stimulated release of PGI₂ from luminally perfused segments of the LAD. This effect was more pronounced in the absence of N ^G-nitro-l-arginine, indicating that PGI₂ release in this preparation may be more sensitive to inhibition by peroxynitrite, the reaction product of NO and O₂ ^–, than to O₂ ^– alone. These findings suggest that, in contrast to NO and PGI₂, the release, and presumably also the mechanism of action, of EDHF in the bovine LAD is resistant to an increase in the local concentration of O₂ ^– or peroxynitrite which is thought to play an important role in coronary heart disease. Received: 27 August 1998 / Accepted: 18 November 1998     

Eukaliuric natriuresis and diuresis in response to disprocynium24: studies on the tubular site of action

We previously described that 1,1’-diisopropyl-2,4’-cyanine (disprocynium24, DP24) exerts an eukaliuric diuresis and natriuresis in the anesthetized rat. The purpose of the present study was to localize the tubular site of action of DP24. Employing micropuncture experiments in anesthetized rats, we first tested the effect of systemic application of DP24 (300 μg/kg+300 μg/kg h, i.v.) on whole kidney excretion rates as well as on fluid, sodium and potassium ion delivery to the early distal tubule (V_ED, Na⁺ _ED, K⁺ _ED). It was found that the eukaliuric diuresis and natriuresis in response to DP24 was accompanied by a substantial increase in V_ED and Na⁺ _ED, suggesting a predominant tubular site of action upstream to the early distal tubule, most likely in the proximal tubule. DP24 caused a comparable fractional, although minor absolute increase in K⁺ _ED as compared to Na⁺ _ED . Second, application of DP24 into the first surface loop of the proximal tubule significantly increased V_ED and Na⁺ _ED at a concentration of about 10^–7 M, indicating that DP24 may act from the intratubular site. Third, microperfusion of tubular segments revealed that effects of DP24 on the proximal convoluted tubule and the loop of Henle accounted for about 70 and 30%, respectively, of its diuretic and natriuretic action upstream to the early distal tubule. With regard to the loop of Henle, the quantitative effect of DP24 on fluid and Na⁺ reabsorption proposed a predominant effect on the straight part of the proximal tubule rather than the thick ascending limb. Intratubular DP24 did not affect reabsorption in the distal tubule. In summary, the present findings indicate that: (1) the diuretic and natriuretic effect of DP24 resides predominantly in the proximal tubule, and (2) DP24 may act from the intratubular site. Since DP24 increased V_ED and Na⁺ _ED without apparently affecting sodium or potassium ion transport in the distal tubule, the mechanism of the eukaliuric response remains unclear. Received: 13 February 1998 / Accepted: 11 May 1998     

Electroencephalographic effects of intravenous nicotine – a dose-response study

Rationale: It has often been demonstrated that both tobacco abstinence and nicotine have effects on the EEG power spectrum and components of the event-related potentials. In contrast, few attempts have been made to establish the dose-response relationship between nicotine and EEG parameters. Objectives: The aim of this study was to investigate the dose-response relationship for EEG and auditory oddball P300 parameters over a wide range of intravenously infused nicotine doses. Method: Fourteen regular smokers who had abstained from nicotine for at least 12 h were given intravenous infusions of 0, 3.5, 7, 14 and 28 μg/kg nicotine over 10 min in a single-blind randomised cross-over design. Parallel recordings of spontaneous EEG, auditory P300 and heart rate, as well as venous blood sampling were made before, during and after nicotine administration. Results: Linear dose-related decreases of delta and theta power were found, along with increases in alpha₂ power and alpha peak frequency. Alpha₁, beta and P300 parameters were unaffected. Conclusion: Our results are consistent with nicotine-dependent changes in EEG measures indicative of arousal. Received: 20 January 1999 / Final version: 25 March 1999     

Comparative bioavailability of two capsule formulations of ofloxacin in healthy volunteers after a single dose administration

Abstract

The bioavailability of two ofloxacin (OFX) tablet formulations (OTT, test formulation from Laboratorio Atral SA - Portugal, and Tarivid, reference formulation from Hoechst AG - Germany) were compared in 24 (12M, 12F) healthy volunteers who received a single oral dose of 200 mg of each formulation in an open, randomized, two-period crossover fashion with a 14 day washout interval between doses. Plasma samples were obtained over a 24 h interval and OFX concentrations were determined by HPLC with UV detection. From the OFX plasma concentration vs time curves, the AUC_[0-24] (area under the concentration vs time curves from 0 to 24 h), AUC_[0-α] (area under the concentration vs time curves extrapolated to infinity), C_max (maximum concentration achieved), t_max (time to achieve C_max), t_1/2 (terminal first order elimination half-life), and elimination constant (K_e) were obtained. All these variables were analyzed using both parametric and non-parametric statistics. The two OFX tablet brands did not show statistically significant differences in bioavailability as assessed by the statistical analysis of AUC_[0-24] (14.8 and 14.7μg h ml^?1, respectively for OTT and Tarivid), AUC_[0-α] (16.0 and 15.6 μg h ml^?1), C_max (2.9 and 3.1 μg/ml), t_max (0.8 and 1.5 h), t_1/2 (5.9 and 5.6 h), and K_e (0.12 and 0.13 h^?1) values. Based on these results and on the United States Food and Drug Administration (FDA) requirements [1993], both formulations were considered to be bioequivalent.     

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

A study was conducted to (i) characterize the multiple-dose pharmacokinetics of oral montelukast sodium (MK-0476), 10 mg d⁻¹ in healthy young subjects (N =12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N =12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d⁻¹ (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration–time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL⁻¹ on days 3–7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1·14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady-state volume of distribution (V_ss), plasma terminal half-life (t_1/2), and mean residence time in the body (MRT^IV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30·8 mL min⁻¹, 9·7 L, 6·7 h, and 5·4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC_0→∞, C_max, t_max, and t_1/2, and the mean plasma concentration–time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age. © 1997 John Wiley & Sons, Ltd.     

酮洛芬缓释片与常释片在健康受试者的药代动力学及生物利用度

目的:酮洛芬缓释片与常释片单次给药的生物利用度和多次给药的峰谷浓度波动大小。方法:采用以萘普生(naproxen)为内标的HPLC测定方法,测定健康男性受试者按交叉试验单剂量和多剂量服用酮洛芬缓释片和常释片后的血中酮洛芬浓度。结果:单剂量服用酮洛芬缓释片和常释片后,常释片的Cmax显著高于缓释片(P<0.01),缓释片给药后的Tmax延迟,t_1/2ke显著延长,相对生物利用度为97.13%。缓释片在稳态时的C_min为0.401μg·mL^-1,而常释片为0.190μg·mL^-1(P<0.01)。在稳态时缓释片的峰谷浓度波动度(DF)、峰谷比(PTR)都显著小于常释片,说明缓释片的峰谷浓度波动程度优于常释片。结论:经统计学检验表明这两种制剂具有生物等效性,该缓释片具有峰谷浓度差异小,波动幅度小的特点,显示出缓释特征。     

高压液相法测定家兔用吡喹酮后的血药浓度及药代动力学参数

本文报道用高压液相法测定家兔用吡喹酮后的血药浓度及药代动力学参数。方法条件:青岛硅胶(5～10μm)柱作吸附层析;正丁醇—氯仿—乙酸乙酯—10%氨水(20:20:60:3)作流动相。荧光检测:λ_ex260nm,λ_em285nm。检测限为20ng吡喹酮,线性范围为0.1～0.9μg/ml血浆。家兔静注吡喹酮后K_α=3.00h^-1,t_1/2(α)=0.23h,K_el=0.28h^-1,t_1/2(β)=2.48h。家兔口服吡喹酮片剂及胶囊后,胶囊的相对生物利用度为片剂的74.8%。     

Physical exercise and binding of digoxin to skeletal muscle — Effect of muscle activation frequency

Summary Ten healthy subjects who had ingested 0.5 mg digoxin daily for at least 10 days, performed a 1-hour bicycle exercise test on two occasions, 24 h after the latest dose, with the same work load but at two different pedalling rates, 40 and 80 rpm. During exercise the mean digoxin concentration in the thigh muscle increased by 8% at 40 rpm (n.s.) and by 29% at 80 rpm (p<0.01). The serum digoxin concentration decreased by 39% at both pedalling rates (p<0.001). The results suggest that the increase in skeletal muscle digoxin concentration during exercise is related to the neuromuscular activation frequency. The digoxin concentration in erythrocytes was measured in 16 healthy subjects before and 1 minute after a 1-hour bicycle exercise test. The erythrocyte digoxin concentration decreased by 12% (p<0.01) during the exercise indicating that the increased uptake of digoxin in skeletal muscle during exercise influences the digoxin concentration in other tissues.     

Intra- and Intersubject Variability: Mixed-Effects Statistical Analysis of Repeated Doses of an Angiotensin Converting Enzyme Inhibitor,CGS 16617

The intrasubject and intersubject variabilities for CGS 16617, an angiotensin converting enzyme inhibitor, were evaluated in an open-label, repeat single-dose bioavailability trial. Eight healthy male volunteers each received a 20-mg oral dose of CGS 16617 as an aqueous solution on four separate occasions. Components of variance were evaluated for a mixed-effects statistical model in which subjects were regarded as a random factor. While intersubject variability was statistically significant (P < 0.05) for all pharmacokinetic variables measured, AUC, C _max, t _1/2, and t _max, its contribution to the total observed variability was relatively small for AUC, t _1/2 and t _max. The proportion of variation due to intrasubject variability was 70, 19, 61, and 72% for AUC, C _max, t _1/2, and t _max, respectively. Ramifications of the large intrasubject source component of variability as related to bioavailability trials and biological variation are discussed.     

Effect of urapidil on steady-state serum digoxin concentration in healthy subjects

Summary In an open, randomized, two-period change-over study the effect of urapidil, an antihypertensive agent, on steady-state serum digoxin levels was investgated in 12 healthy male volunteers. The subjects were given digoxin 0.25 mg once daily for 4 days to produce a steady-state digoxin level in serum. At the end of that time the subjects received either digoxin monotherapy or digoxin and concomitant treatment with urapidil 60 mg b.d. for a further 4 days. Subsequently the treatments were changed over.The absorption characteristics C_max and t_max of digoxin were not altered by concomitant urapidil treatment. The geometric mean and nonparametric 95% confidence limits of digoxin relative bioavailability were 97% (93%–103%).Therefore, concomitant administration of urapidil with digoxin treatments did not appear to alter the rate and extent of absorption of the glycoside.     

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.     

Lack of an effect of anacetrapib on the pharmacokinetics of digoxin in healthy subjects

Anacetrapib is currently being developed for the oral treatment of dyslipidemia. A clinical study was conducted in healthy subjects to assess the potential for an interaction with orally administered digoxin. Anacetrapib was generally well tolerated when co‐administered with digoxin in the healthy subjects in this study. The geometric mean ratios (GMR) for (digoxin + anacetrapib/digoxin alone) and 90% confidence intervals (CIs) for digoxin AUC_0‐last and AUC_0‐∞ were 1.05 (0.96, 1.15) and 1.07 (0.98, 1.17), respectively, both being contained in the accepted interval of bioequivalence (0.80, 1.25), the primary hypothesis of the study. The GMR (digoxin + anacetrapib /digoxin alone) and 90% CIs for digoxin C_max were 1.23 (1.14, 1.32). Median T_max and mean apparent terminal t_½ of digoxin were comparable between the two treatments. The single‐dose pharmacokinetics of orally administered digoxin were not meaningfully affected by multiple‐dose administration of anacetrapib, indicating that anacetrapib does not meaningfully inhibit P‐glycoprotein. Thus, no dosage adjustment for digoxin is necessary when co‐administered with anacetrapib. Copyright © 2011 John Wiley & Sons, Ltd.