Human target validation of phosphoinositide 3-kinase (PI3K)ß: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kß inhibitor.

BACKGROUND: Based on in vitro and animal data, PI3Kß is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear. OBJECTIVE: To strengthen the PI3Kß target validation using the novel, short-acting inhibitor AZD6482. METHODS AND RESULTS: AZD6482 is a potent, selective and ATP competitive PI3Kß inhibitor (IC(50) 0.01 µm). A maximal anti-platelet effect was achieved at 1 µm in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti-thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3-h infusion. The ex vivo anti-platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin-induced human adipocyte glucose uptake in vitro (IC(50) of 4.4 µm). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 µm but reduced by about 60% at a plasma exposure of 27 µm. In man, the homeostasis model analysis (HOMA) index increased by about 10-20% at the highest plasma concentration of 5.3 µm. CONCLUSIONS: This is the first human target validation for PI3Kß inhibition as anti-platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at 'supratherapeutic' plasma concentrations may attenuate insulin signaling, most likely through PI3Kα inhibition.

Bioavailability and half-life of decabromodiphenyl ether (BDE-209) in rat.

1. The absorption of the flame retardant decabromodiphenyl ether (BDE-209) has been shown by its detection in human plasma, but reported experimental data on its determined in rat, and qualitative analyses by GC/MS of metabolites in plasma were performed. The relative amount of phenolic metabolites was determined in a rat plasma sample obtained after administration of radiolabelled BDE-209. 2. The bioavailability of parent BDE-209 was calculated to be about 26% in rat. The concentrations of phenolic radioactivity in plasma 3 and 7 days after dosing were four times higher than those of the neutral compounds, i.e. parent compound, indicating absorption in rat are inconsistent. The bioavailability and half-life were therefore that total absorption was higher than 26%. 3. Thirteen phenolic metabolites were determined in the plasma and the major phenolic metabolites were characterized as a hydroxy-octaBDE, a hydroxy-nonaBDE and a hydroxy-methoxy-hexaBDE (guaiacol-type). The exposure to the phenolic metabolites seemed higher than the parent compound, BDE-209. 4. The initial elimination phase in plasma t1/2alpha for BDE-209 was 2 h, implying a rapid distribution of BDE-209 to well-perfused tissues. The distribution volume at steady state was 1.4 l kg-1, implying a low tendency for distribution to adipose tissue. The terminal t1/2 for BDE-209 in the intravenously dosed rat was calculated as 2.5 days (58 h).

The effectiveness of intravenous ketamine and lidocaine on peripheral neuropathic pain.

BACKGROUND: Neuropathic pain is often severe and resistant to pharmacological treatment. The aims of the present study were to assess the analgesic effect of ketamine and lidocaine and to investigate if measurement of different variables of sensibility could be used to identify responders. We also wanted to study if treatment resulted in changes of sensibility. METHODS: Twelve patients with long-lasting peripheral neuropathic pain of traumatic origin were included. The effects of ketamine hydrochloride (Ketalar, Parke Davis) 0.4 mg/kg and lidocaine hydrochloride (Xylocain, Astra) 2.5 mg/kg were investigated. Saline was used as placebo. The intensity of continuous pain was measured by a visual analogue scale (VAS). Warm and cold perception as well as heat and cold pain thresholds were assessed. Sensibility to touch was also tested. Systemic plasma concentrations of lidocaine and ketamine were assessed. RESULTS: The mean reduction in VAS-scores was 55%, 34% and 22% for ketamine, lidocaine and placebo, respectively. A significant difference was registered between ketamine and placebo (P = 0.009). Response to treatment (50% reduction in VAS-score during infusion) was recorded in 7/12 in the ketamine, 4/12 in the lidocaine and 2/12 in the placebo group. Quantitative sensory testing (QST) of thermal sensitivity and sensory tests for mechanical stimuli could not separate responders from non-responders and neither were the results from these assessments changed by the infusion of the drugs. Lidocaine and particularly ketamine were associated with frequent side-effects, the most common being somnolence and dizziness. CONCLUSION: Ketamine showed a significant analgesic effect. The clinical usefulness is, however, limited by disturbing side-effects.

Epidural infusion of ropivacaine for postoperative analgesia after major orthopedic surgery: pharmacokinetic evaluation.

BACKGROUND: Changing plasma protein concentrations may affect the protein binding and pharmacokinetics of drugs in the postoperative phase. Therefore, the authors evaluated the pharmacokinetics of ropivacaine, administered by 72-h epidural infusion to provide postoperative analgesia. METHODS: Twenty-eight patients, scheduled for major orthopedic surgery during combined epidural and general anesthesia received a bolus dose of ropivacaine (50 or 75 mg), followed by constant-rate (10 ml/h) epidural infusion of ropivacaine 2 mg/ml (group 1) or 3 mg/ml (group 2). Total and unbound plasma concentrations of ropivacaine and pipecoloxylidide and plasma concentrations of alpha1-acid glycoprotein were determined. In addition, the urinary excretion of ropivacaine and major metabolites was measured. RESULTS: Total plasma concentrations of ropivacaine increased steadily during the infusion, reaching 2.7 +/- 0.7 and 2.9 +/- 0.5 mg/l in groups 1 and 2 after 72 h constant-rate infusion. Unbound ropivacaine concentrations reached average steady state levels of approximately 0.06 and 0.07 mg/l. Total and unbound concentrations of pipecoloxylidide increased to 1.0 +/- 0.4 and 0.4 +/- 0.2 mg/l (group 1) and 1.2 +/- 0.4 and 0.5 +/- 0.1 mg/l (group 2) after 72 h infusion. alpha1-Acid glycoprotein concentrations initially decreased, but thereafter increased steadily to approximately twice the baseline values. CONCLUSIONS: Postoperative increases in plasma alpha1-acid glycoprotein concentrations enhance the protein binding of ropivacaine and pipecoloxylidide, causing divergence of total and unbound plasma concentrations.

Ropivacaine 0.25% and 0.5%, but not 0.125%, provide effective wound infiltration analgesia after outpatient hernia repair, but with sustained plasma drug levels.

BACKGROUND AND OBJECTIVES: Ropivacaine is a long-acting local anesthetic similar to bupivacaine, but with lower cardiac toxicity and intrinsic vasoconstrictive properties that may reduce the risk and extent of systemic plasma absorption. Plasma levels and risks are associated with the total dose used and the extent of absorption, with lower doses potentially representing less risk. Although both 0.5% and 0.75% ropivacaine provide adequate analgesia for wound infiltration after hernia repair, the efficacy of lower doses and the early systemic absorption have not been reported. METHODS: We studied postoperative pain and systemic plasma levels following either the injection of 30 mL of saline or 0.125%, 0.25%, or 0.5% ropivacaine into the wounds in 110 healthy patients following hernia repair under spinal anesthesia. Pain was assessed using visual analog scale (VAS) scores and algometer readings at rest and after coughing, and oral analgesic requirements were assessed in the first 5 hours after surgery and for the week after discharge. RESULTS: Both 0.25% and 0.5% ropivacaine provided pain relief following surgery when compared with saline or 0.125%. No adverse reactions to the drug were reported in any group. Plasma levels of ropivacaine peaked between 30 and 60 minutes, at 0.109, 0.249, and 0.399 mg/L for 0.125%, 0.25%, and 0.5% concentrations, respectively. Although the levels were below those producing clinical symptoms, they remained elevated for the entire 2-hour sampling period. This implies an absorption-dependent elimination which is substantially longer than reported with other routes of injection. CONCLUSIONS: Ropivacaine 0.25% and 0.5% is adequate for pain relief after outpatient hernia repair, whereas the 0.125% solution is no more effective than saline. Prolonged systemic absorption from peripheral injection may be associated with prolonged elevations of plasma concentrations, which potentially could be associated with unexpectedly high plasma levels if repeated injections are performed in the perioperative period with higher concentrations or doses.

Pharmacokinetics and clinical effect during continuous epidural infusion with ropivacaine 2.5 mg/ml or bupivacaine 2.5 mg/ml for labour pain relief.

BACKGROUND: Ropivacaine has shown less systemic toxicity than bupivacaine, and comparatively low muscle-blocking properties could constitute another advantage when used epidurally for obstetric pain relief. We aimed primarily to compare maternal and foetal drug disposition following continuous epidural infusion of ropivacaine or bupivacaine. METHODS: Twenty-four full-term, nulliparous women were randomized to continuous epidural infusion (10 ml/h) of ropivacaine 2.5 mg/ml or bupivacaine 2.5 mg/ml for labour pain relief in a double-blind, parallel-group design. Maternal blood samples were collected up to 24 h after the end of infusion as well as taken from the umbilical cord at the time of delivery. Sensory and motor block as well as analgesia were assessed. All the women were monitored by cardiotocography and neonatal assessment was performed. RESULTS: The sensory block was adequate for both drugs. Higher plasma levels (total and free) were seen with ropivacaine, although the infusion with bupivacaine continued on average for about 2 hours longer. However, the ratios between maternal and umbilical blood concentrations were similar for both drugs. Normal neonatal Apgar and neonatal adaptive capacity scores (NACS) were found in both groups. CONCLUSION: A continuous epidural infusion of 25 mg/h ropivacaine or bupivacaine both produced good labour pain relief. Higher total and free plasma concentrations were seen for ropivacaine. The ratios between maternal and umbilical plasma levels were similar for both drugs.

High-dose ropivacaine wound infiltration for pain relief after inguinal hernia repair: a clinical and pharmacokinetic evaluation.

BACKGROUND AND OBJECTIVES: Early data on ropivacaine, a recently introduced local anesthetic, indicate a longer duration of skin analgesia than with bupivacaine, along with lower toxicity. The objective of this study was to evaluate ropivacaine 7.5 mg/mL for wound infiltration pain relief after hernia surgery, in higher doses than used before, in an open, nonrandomized design. METHODS: Twenty otherwise healthy men underwent elective unilateral open hernia repair by the same surgeon. General anesthesia was used during surgery, and infiltration of the operating field with 300 mg (n = 10) or 375 mg (n = 10) ropivacaine, 7.5 mg/mL, was employed for postoperative pain relief. Any sign of an adverse event was recorded. Plasma concentrations of ropivacaine were monitored. Pain at rest and on mobilization was regularly assessed over 24 hours by a visual analog scale. Patients' ability to walk and void and the need for supplementary analgesics were recorded. RESULTS: No serious adverse effects occurred. Plasma concentrations showed large variations but no toxic levels. No significant differences between the two groups were detected in pain scores which were low in both groups, at rest or on mobilization, or in the consumption of supplementary analgesics. At 4 hours, 19 patients were able to walk. Within 8 hours of surgery, all patients had passed urine without any problem. Wound healing was normal. CONCLUSIONS: Infiltration of ropivacaine 7.5 mg/mL during hernia surgery can be employed safely in doses of 300 mg and 375 mg to control pain after hernia surgery. The lower dose is recommended, since the higher one did not give any clinically relevant advantages.

Pharmacokinetics and efficacy of long-term epidural ropivacaine infusion for postoperative analgesia.

UNLABELLED: The aim of this study was to evaluate the pharmacokinetics and efficacy of the new local anesthetic ropivacaine when used for epidural infusion for up to 72 h after major orthopedic surgery. Immediately after surgery, an epidural infusion of ropivacaine 2 mg/mL was begun at a rate of 6 mL/h in 11 patients. The infusion rate was then adjusted according to patient analgesic needs or side effects. Blood samples were taken during and after the infusion to determine total and unbound ropivacaine and alpha1-acid glycoprotein (AAG) concentrations. Patients were assessed regularly for sensory and motor block and pain using a visual analog scale (VAS) score (0-100 mm). Ten patients received 63-72 h of infusion. Total plasma concentrations of ropivacaine and binding protein (AAG) increased during the infusion such that free concentrations plateaued or began to fall over time. VAS values during mobilization were less than 40 mm in 93% of patients. The majority of patients had no measurable motor block once the surgical block had regressed. When epidural ropivacaine was titrated to achieve a stable sensory block, there was a low incidence of motor block, and free plasma ropivacaine levels were well below the toxic range. IMPLICATIONS: The pharmacokinetics of continuous epidural infusions of ropivacaine are described in patients for up to 72 h postoperatively. Clinical efficacy and side effects are also reported. An understanding of the plasma concentrations obtained and modes of elimination during prolonged epidural infusion is important for safe, routine clinical use in postoperative analgesia.

Ropivacaine 7.5 mg/ml for elective caesarean section. A clinical and pharmacokinetic comparison of 150 mg and 187.5 mg.

BACKGROUND: The new, long-acting local anaesthetic ropivacaine has shown less systemic toxicity than bupivacaine and a concentration of 7.5 mg/ml can therefore be used for epidural anaesthesia in Caesarean section. The present pilot study was undertaken to find indications for an optimal dosage by comparing the clinical effects, quality of anaesthesia and pharmacokinetics of ropivacaine 150 mg (lower dose = LD) vs 187.5 mg (higher dose = HD) for women undergoing elective Caesarean section under epidural anaesthesia. METHODS: Sixteen full-term women scheduled for elective Caesarean section in two equal-sized consecutive groups received 20 or 25 ml ropivacaine epidurally in this non-randomised, open study. Study parameters included sensory and motor blockade, circulatory response, intraoperative pain and discomfort, neonatal evaluation and pharmacokinetic determinations. RESULTS: Block height varied between T5 and T2 in the LD group, whereas the HD group produced 4 unnecessarily high blocks (C8 in 3 women and C7 in 1 woman). Surgical anaesthesia was excellent in both groups. Circulatory stability was pronounced in the LD group (no ephedrine given), while 4 women required ephedrine in the HD group. Neonatal outcome as judged by Apgar scores; umbilical blood gas determinations and NACS scores were excellent in both groups. The plasma concentration-time profiles indicated linearity in the concentration range studied, with similar clearance values to those reported previously. Placental drug equilibrium was rapid; however, the foetal drug exposure depended on intrauterine exposure time. CONCLUSIONS: 20-25 ml ropivacaine 7.5 mg/ml produced very satisfactory conditions for elective Caesarean section under epidural anaesthesia. In this small population, 150 mg ropivacaine seemed optimal, while 187.5 mg produced unnecessarily extended block height in 50% of the women.

Intraindividual and interindividual variability in the disposition of the local anesthetic ropivacaine in healthy subjects.

To predict the risk of adverse reactions to local anaesthetics used in clinical practice, it is crucial to know whether any nonlinearity exists in their pharmacokinetics. The disposition of ropivacaine, a new local anesthetic agent, was evaluated in healthy subjects on the basis of plasma levels in the concentration range obtained after regional anaesthesia. Three intravenous doses of ropivacaine hydrochloride (20, 40, and 80 mg) were given in a double-blind, randomized, complete crossover design. Analysis of variance was used to assess the importance of intra- versus interindividual variability in the basic pharmacokinetics. The mean plasma clearance (400 ml/min), volume of distribution at steady state (40 l), and terminal half-life (1.7 h) were similar, irrespective of dose. The intersubject variability for these parameters was higher than the intrasubject variability. A slight increase in free fraction (15%) with increasing dose might indicate that the lower limit for saturation of protein binding may be reached at the higher plasma levels. One subject (80 mg) reported numbness of the lower lip 2 min after the end of the infusion, which may be a sign of systemic CNS toxicity. The total and free plasma concentration was extrapolated to 1.7 and 0.08 mg/l, respectively.

Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers.

BACKGROUND: For local anesthetics, the process of removal from the site of administration influences the duration of anesthesia and the risk for systemic toxicity to develop. The systemic absorption of epidural ropivacaine and the time profile of sensory and motor block were studied in healthy volunteers. METHODS: Nine persons simultaneously received 150 mg ropivacaine hydrochloride (7.5 mg/ml) epidurally and 40 mg deuterium-labeled (2H3)ropivacaine hydrochloride (0.25 mg/ml) intravenously. Peripheral arterial and venous plasma samples were collected, and assessments of sensory and motor block were made. RESULTS: The arterial plasma concentrations increased faster than the venous concentrations, with 50% higher maximum concentrations after both intravenous and epidural administration. The absorption was biphasic. A correlation was seen between the duration of sensory block and the slower absorption half-life; that is, the longer the half-life, the longer the duration. The extent of spread varied among the volunteers, with the median upper block level not exceeding T12. The motor block (Bromage score 1) was of slower onset (median, 0.4 h) and of shorter duration (median, 4.1 h) than the sensory block (onset, 0.2 h; duration, 6.5 h at L2 medians). CONCLUSIONS: As much as 50% differences were seen in the arteriovenous plasma concentrations of ropivacaine during the first hour, which has implications for the interpretation of systemic toxic plasma concentrations. The absorption into the general circulation was biphasic, with a correlation between the sensory block and the slower absorption half-life. A faster onset and a longer duration of sensory compared with motor block was seen.

Pharmacokinetics of ropivacaine and bupivacaine during 21 hours of continuous epidural infusion in healthy male volunteers.

The aim of the present study was to evaluate the pharmacokinetics of ropivacaine and to compare the results with those of bupivacaine during prolonged epidural infusion. Ropivacaine 1, 2, or 3 mg/mL (0.1%, 0.2%, or 0.3%), bupivacaine 2.5 mg/mL (0.25%), or placebo (sodium chloride 0.9%) was given randomly and in a double-blind manner to five parallel treatment groups (37 healthy volunteers) as a continuous epidural infusion for 21 h. A 10-mL epidural bolus dose was first given, and the epidural infusion was started immediately afterward. The subjects received 10 mL/h corresponding to infusion rates of 10, 20, or 30 mg/h ropivacaine and 25 mg/h bupivacaine, respectively. Peripheral blood samples for measurements of ropivacaine or bupivacaine were taken during a 25-h period. The total plasma concentration increased continuously but seemed to reach a plateau (C5-10h) after approximately 5 h infusion, remaining fairly constant up to approximately 10 h after the start of administration. The C5-10h values were proportional to the dose of ropivacaine and were estimated as 0.3, 0.6, and 0.9 mg/L, and for bupivacaine as 0.7 mg/L. During the subsequent infusion the plasma concentration increased, with maximum plasma levels at the end of the infusion and with corresponding values of 0.4, 0.9, 1.2, and 0.9 mg/L. The highest individual plasma concentration was 1.7 mg/L (20 mg/h), and no patient showed signs of toxic systemic plasma levels. The free concentrations also increased continuously during the infusion. The free fraction was independent of the dose (6.1% for ropivacaine and 4.8% for bupivacaine).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of ropivacaine and bupivacaine for bilateral intercostal blockade in healthy male volunteers.

BACKGROUND: Intercostal blockade produces the highest serum local anesthetic concentrations of all regional anesthetic techniques. The purpose of this study was to determine the pharmacokinetic properties of ropivacaine and bupivacaine after bilateral intercostal blockade. METHODS: The pharmacokinetics of ropivacaine (n = 7) and bupivacaine (n = 7) were determined in adult human volunteers from venous samples drawn over 24 h after bilateral intercostal blockade of T5-T11 with 140 mg of either drug (0.25% plain solutions, 56 ml). Sensory (pinprick, temperature, and touch) and motor blockade (RAM-test and integrated electromyography) were assessed every 2 h. RESULTS: There was no significant difference between the maximum plasma concentrations (Cmax) obtained for either drug (ropivacaine 1.1 +/- 0.4 microgram/ml, bupivacaine 0.9 +/- 0.2 microgram/ml, P = 0.39), and there were no toxic signs observed in the obtained plasma concentration ranges. Plasma concentrations tended to peak (tmax) earlier with ropivacaine (21 +/- 9 versus 30 +/- 8 min, P = 0.09). The terminal half-life (t1/2 beta) of ropivacaine (2.3 +/- 0.8 h) was significantly less than that for bupivacaine (4.6 +/- 2.6 h, P = 0.04). Sensory blockade measured by pinprick was of shorter duration with ropivacaine (6.0 +/- 2.5 h versus bupivacaine 10.0 +/- 3.0 h; P < 0.001). Likewise, motor blockade was less intense and of shorter duration for ropivacaine by RAM-test (P = 0.02). CONCLUSIONS: The results of this pharmacokinetic study indicate that 0.25% ropivacaine and 0.25% bupivacaine (56 ml, 140 mg) produce peak plasma levels less than those considered toxic when used in bilateral intercostal blockade. Studies of ropivacaine for intercostal blockade in surgical patients are necessary before the optimum concentration for efficacy and anesthetic/analgesic duration is identified.

Efficacy and kinetics of extradural ropivacaine: comparison with bupivacaine.

Ninety-one patients were allocated randomly to three groups to receive 1% ropivacaine 10 ml, 0.5% ropivacaine 20 ml or 0.5% bupivacaine 20 ml extradurally. Intermittent sensory (pinprick) and motor (Bromage scale) assessments of the block produced were recorded, with an assessment of the quality of the block and the requirement for supplementary analgesia. There was little difference between the groups in frequency, onset, duration or spread of sensory block. However, the motor block produced by 0.5% ropivacaine was less intense and of shorter duration than that with bupivacaine. The block produced by the smaller volume of ropivacaine was less reliable clinically than the larger, more dilute, solution and more anaesthetic supplements were required in that group. Cardiovascular changes were similar in all three groups. The peak plasma concentration of ropivacaine was significantly greater and T1/2 significantly shorter than those of bupivacaine, although no patient showed any features of systemic toxicity. The systemic kinetics of ropivacaine were not influenced significantly by varying the concentration or volume administered.

Pharmacokinetics of oral tiopronin.

Ten healthy subjects were given 500 mg (3064 mumol) tiopronin, or 2-mercaptopropionylglycine (2-MPG) by mouth. Cmax was reached after 3-6 h, and after a shorter beta-phase a long terminal half-life of 53 h of total tiopronin was found. Tiopronin measured as unbound (non-protein-bound) drug disappeared more rapidly from plasma, with a calculated t1/2 of 1.8 h. Mean residence time was higher (58 h) when calculated as total tiopronin than as unbound tiopronin (6 h), and this was also the case for the volume of distribution (V lambda = 455 l vs V lambda,u = 41 l). The results indicate extensive protein binding in plasma and a deep pool of tissue bound tiopronin after the first absorption and distribution phases. Absolute bioavailability (f) was 63%, and bioavailability calculated from urinary excretion was 47%, which are well correlated with each other. Urinary excretion was mainly confined to the first 6 h (74%) and was almost complete (98%) within 12 h. We conclude that the maximal absorption of the tiopronin was late, protein and tissue binding of the drug were high and its bioavailability varied. The renal excretion of low molecular weight tiopronin occurred early, which implies that the drug should be given in divided doses, at least twice daily, for optimal efficiency in the treatment of cystinuria.

Pharmacokinetics and bioavailability of 2-mercaptopropionylglycine administered intravenously and orally in dogs.

The pharmacokinetic disposition of 2-mercaptopropionylglycine (2-MPG) given as a single intravenous injection and/or as a single oral dose was studied in 9 normal and 13 cystinuric dogs. After intravenous injection of approximately 10 or 20 mg/kg body weight the pharmacokinetics were best described by a three-exponential function. The first phase involved a distribution process apparently including establishment of drug-plasma protein and drug-tissue binding. The second phase involved rapid renal elimination and 60% of the drug was excreted within 3 h of administration. There was also a slow terminal third phase with a long half-life after both intravenous (t1/2 = 23 h) and oral (t1/2 = 22 h) administration. No dose dependency was observed. A deep pool of reversibly tissue-bound 2-MPG was indicated by a Vss of 3.3 +/- 0.9 l/kg body weight and the long terminal elimination phase. Total clearance was estimated as 4.1 +/- 0.9 ml/min/kg body weight. 2-MPG was eliminated mainly by renal excretion, but there was a difference in recovery of dose between normal and cystinuric dogs. During the first 24 h after intravenous and oral administration, 69% and 54%, respectively, of the drug was recovered in the urine of normal dogs. The corresponding figures in cystinuric dogs were 44% and 29%, respectively. The absolute bioavailability (FAUC) was 88 +/- 20% in normal dogs.

Pharmacokinetics of intravenous 2-mercaptopropionylglycine in man.

The pharmacokinetics of 2-mercaptopropionylglycine (2-MPG) was studied in ten healthy volunteers after a single i.v. injection of 250 mg (1532 mumol). The total and non-protein-bound concentrations versus time curves were best described by a three-exponential function with terminal half-lives of 55 and 59 h respectively. Body clearance based upon the total concentration was estimated to be 105 and 231 ml/min based on the non-protein-bound 2-MPG. The corresponding values for Vss were 99 l and Vss,n 173 l, and for V gamma 485 l and V gamma,n 1121 l respectively. 75% of the dose was excreted in the urine, mainly during the first 6 h after injection. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased.

Amikacin once daily: a new dosing regimen based on drug pharmacokinetics.

Once-daily dosing of amikacin is a novel therapy regimen which seems pharmacokinetically appropriate for the primary group of patients considered for aminoglycoside therapy. In this study of 29 elderly patients with serious infections, amikacin 11 mg/kg or 15 mg/kg bw was administered as a short-term (30 min) intravenous infusion. The amikacin serum concentration-time profile was best described by a bi-exponential equation with a half-life of about 4.8 h. A triexponential equation was not applicable because the slow terminal elimination phase was not detected during the 24 h dosing interval. In practice, a uni-exponential equation is often used, and this may lead to incorrect conclusions about the elimination rate of amikacin. Amikacin clearance provides more direct information about elimination of amikacin than does serum half-life. Thus, there was a better correlation between the individual amikacin clearances and creatinine clearances (r = 0.89), than between the serum half-lives of amikacin and the creatinine clearances (r = 0.71). For elderly patients a smaller dose of amikacin than the regular daily dose of 15 mg/kg bw, i.e. about 11 mg/kg bw, seems recommendable, when it is given once daily. From the data obtained it is also obvious that once-daily dosing of amikacin does not eliminate the need for checking serum concentrations of the drug.

Hepatic and renal clearances of probenecid in the rat.

The elimination kinetics of probenecid in the rat was studied by using an in vitro liver perfusion system to estimate its basic elimination and in vivo to estimate its renal excretion by catheterization of the urinary bladder. In the liver perfusion study different amounts of probenecid were added to the perfusion medium yielding different initial concentrations (40, 200 and 400 micrograms/ml), and 4 different intravenous bolus doses (50, 75, 100 and 200 mg/kg) were administered in vivo to rats in order to evaluate the renal excretion. The results obtained were described by one-compartment models, with Michaelis-Menten elimination by the liver Vm = 67.4 +/- 14.0 (SD) micrograms/min and a slightly decreasing Km with increasing initial concentrations [from 76.5 +/- 9.0 to 53.2 +/- (SD) 18.4 micrograms/ml]. The excretion by the kidney was characterized by a saturable pathway in parallel with first-order elimination, the maximum rate of the active transports Tm = 0.04 +/- (SD) 0.09 micrograms/min, Km,r = 100.3 +/- (SD) 12.3 micrograms/ml and a linear renal clearance of 0.0008 +/- (SD) 0.0002 ml/min.