Time Course Of Plasma Concentrations Research Articles

Influence of chronic hepatic failure on disposition kinetics of valproate excretion through a phase II reaction in rats treated with carbon tetrachloride

The influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reaction was examined in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among the control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was reduced significantly, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentration-time curve was decreased significantly in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G.

The Connection Between the Steady State (Vss) and Terminal (Vβ) Volumes of Distribution in Linear Pharmacokinetics and The General Proof That Vβ ≥ Vss

The steady state and terminal (area) volumes of distribution are important pharmacokinetic parameters defined as the ratio of the total quantity of drug in the body, Ab(t), to drug plasma concentration Cp(t) at steady state and the terminal phase of drug elimination, respectively. The general equations for the approach of Cp(t), Ab(t) and the distribution volume Ab(t)/Cp(t) to the steady state values (for a continuous constant rate drug infusion) are derived. It is shown that the time course of Ab(t) near the asymptotic steady state value depends on both the terminal and steady state volumes of distribution, and an accurate equation to determine the time required to reach the steady state is obtained. For a general linear pharmacokinetic system (i.e., with possible drug elimination at any state from any compartment and drug exchange between compartments) it is proven that Vβ ≥ Vss. A physiologically determined feature, which is the drug input into plasma for reaching the steady state or terminal phase, underlies the proof. If the steady state is reached by a continuous input of drug into some compartment other than plasma, and the terminal volume of distribution is considered after dosing of a drug in the same compartment, then both cases Vss ≶ Vβ are possible. It is shown that the general exponential series for Cp(t) after intravenous bolus dose may have negative pre‐exponents, unlike a common assumption that all pre‐exponents should be positive. Its is figured out that the commonly used equations for the estimation of Vss and Vβ (Vss = D · AUMC/AUC2 and Vβ = D/(AUC · β) may yield Vss > Vβ for a linear pharmacokinetic system, contrary to the usual statement (Vss < Vβ) and its seemingly simple proof, which has a flaw. It is shown that the time required to reach the steady state concentration of drug in plasma could be much shorter than a commonly used estimation of 5t1/2, where t1/2 is the terminal half‐life obtained from the intravenous bolus drug plasma concentration time course.

Effects of Long‐term 4‐Aminopyridine Therapy on Glucose Tolerance and Glucokinetics in Patients with Spinal Cord Injury

To assess the effects of the potassium channel blocker, 4-aminopyridine, on glucose tolerance and glucokinetics in patients with spinal cord injury. Prospective, dose level-blinded study. University-affiliated, tertiary-level care, Veterans Affairs medical center, and a university-affiliated research center. Thirty-one patients with spinal cord injury of more than 1 year's duration. In a fasting state, patients ingested 75 g of glucose and completed a 5-hour oral glucose tolerance test before and after 6 months of treatment with an oral, immediate-release formulation of 4-aminopyridine. The time course of glucose plasma concentrations during the oral glucose tolerance tests was profiled for each patient, and glucokinetic parameters were estimated. Results were compared at baseline and after 6 months of treatment with 4-aminopyridine. Of the 31 patients, 29 (94%) had impaired glucose tolerance at baseline. After 6 months of treatment with 4-aminopyridine, 12 (41%) of the 29 patients had a 2-hour postprandial glucose level that no longer supported a diagnosis of impaired glucose tolerance. No significant changes or clinically important trends were seen in fasting blood glucose concentrations or in other glucokinetic parameters in these patients. The long-term administration of an oral, immediate-release formulation of 4-aminopyridine to patients with longstanding spinal cord injury was associated with readily discernible, potentially clinically significant improvements in glucose tolerance. Because impaired glucose tolerance is a common finding in patients with spinal cord injury, more research, including randomized controlled trials with large study populations, is warranted on this potential treatment.

Predictive performance of the Domino, Hijazi, and Clements models during low-dose target-controlled ketamine infusions in healthy volunteers

Healthy volunteers received low-dose target-controlled infusions (TCI) of ketamine controlled by the Domino model while cognitive function tests and functional neuroimaging were performed. The aim of the current study was to assess the predictive performance of the Domino model during these studies, and compare it with that of three other ketamine models. Fifty-eight volunteers received ketamine administered by a TCI device on one or more occasions at target concentrations of either 50, 100, or 200 ng ml-1. At each target concentration, two or three venous blood samples were withdrawn during infusion, with a further sample after the infusion ended. Ketamine assays were performed by gas chromatography. The plasma concentration time courses predicted by the Hijazi, Clements 125, and Clements 250 models were calculated retrospectively, and the predictive performance of each of the models was assessed using Varvel methodology. For the Domino model, bias, inaccuracy, wobble, and divergence were - 2.7%, 33.9%, 24.2%, and 0.1463% h-1, respectively. There was a systematic increase in performance error over time. The Clements 250 model performed best by all criteria, whereas the Hijazi model performed least well by all criteria except for bias. Performance of the Domino model during control of low-dose ketamine infusions was sub-optimal. The Clements 250 model may be a better model for controlling low-dose TCI ketamine administration.

Modeling Methadone Pharmacokinetics in Rats in Presence of P-glycoprotein Inhibitor Valspodar

To quantify the in vivo role of P-glycoprotein (P-gp) in the pharmacokinetics of methadone after intravenous and oral administration, using valspodar as a P-gp inhibitor. Methadone plasma concentrations after intravenous (0.35 mg/kg) and oral (6 mg/kg) administration were analyzed, in absence and presence of valspodar, using nonlinear mixed effects modeling (NONMEM V). Non-parametric bootstrap analysis and posterior predictive check were employed as model evaluation techniques. The pharmacokinetics of methadone in the rat was successfully modeled using a two-compartmental model with a linear elimination from the central compartment and a first-order absorption process with lag time. Valspodar increased methadone F by 122% (95%CI: 34-269%) and decreased the V ( c ) and V ( p ) by 35% (95%CI: 16-49%) and 81% (95%CI: 63-93%), respectively. No effect of valspodar on other pharmacokinetic parameters was discernible. The non-parametric bootstrap analysis confirmed the absence of bias on the parameter estimates, and visual predictive check evidence the adequacy of the model to reproduce the observed time course of methadone plasma concentrations. Valspodar increased methadone's bioavailability as consequence of P-gp inhibition, which resulted in an increased analgesic effect of methadone.

Tissue and plasma concentrations of cephuroxime during cardiac surgery in cardiopulmonary bypass — a microdialysis study

Wound and mediastinal infections are still very serious complications of open-heart surgery, in spite of the use of prophylactic antibiotics. The use of cardiopulmonary bypass (CPB) is associated with profound physiological changes affecting the pharmacokinetic behaviour of antibiotics. The aim of this pilot study was to monitor the tissue concentrations of cephuroxime (prophylactic antibiotic) in skeletal muscle during cardiac surgery using CPB by interstitial microdialysis. These concentrations were compared with plasma concentrations of cephuroxime. Nine adult patients operated on using CPB were enrolled in this study. Cephuroxime was used as a prophylactic antibiotic (1st dose - 3 g of cefuroxime i.v. with anesthesia induction, 2nd dose - 1.5 g i.v. after CPB with protamine sulphate, 3rd dose - 1.5 g i.v. 8 hours after the surgery). Interstitial microdialysis was performed by probe CMA 60 (CMA Microdialysis AB, Sweden) inserted into the patient's deltoid muscle. Concentrations of cephuroxime in dialysates and in plasma were determined by the modified fluid chromatography method. The unbound cephuroxime fraction in plasma was obtained by using an ultrafiltration method. Samples of dialysates were collected at the following intervals: before CPB, each 30 minutes of CPB, at the end of CPB. Samples of blood were collected at these intervals: incision, start of CPB, each 30 minutes of CPB, at the end of CPB, at the end of surgery. Concentrations of cephuroxime in tissue were corrected by in vivo recoveries of the microdialysis probes. Plasma concentrations of cephuroxime were 163.5 +/- 40.1, 79.3 +/- 17.4, 73.7 +/- 16.8, 66.1 +/- 18.3, 57.0 +/- 10.9, 120.7 +/- 29.9 (mg L(-1)) and concentrations of free plasma fraction of cephuroxime were 119.5 +/- 35.2, 67.8 +/- 15.5, 66.0 +/- 12.5, 54.8 +/- 12.2, 49.6 +/- 9.8, 102.6 +/-26.0 (mg L(-1)). The concentrations of cephuroxime in dialysates were 44.3 +/- 15.7, 36.1 +/- 11.6, 31.9 +/- 9.3, 34.6 +/- 12.3, 27.6 +/-12.9, 56.7 +/- 17.6 (mg L(-1)). The mean in vivo recovery of cephuroxime in this study was 30%. Corrected concentrations (calculated by in vivo recovery) of cephuroxime in skeletal muscle were 148, 120, 106, 115, 92, 189 (mg L(-l)). Our preliminary results show that CPB can modify the time course of cephuroxime plasma and tissue concentrations. A decrease in plasma drug concentrations occurred at the start of CPB and lasted until CPB ended. An increase in plasma concentrations corresponds to the second drug dose after CPB. The concentrations of cephuroxime in skeletal muscle (corrected by recovery) during CPB are higher than plasma concentrations. It is influenced by important changes during CPB; closely associated with hemodilution, a shift of intravascular volume, solutes and albumin to the extravascular space and inconstant protein binding of cephuroxime during operation.

Optimal Design for Multiresponse Pharmacokinetic–Pharmacodynamic Models – Dealing with Unbalanced Designs

This paper addresses the problem of determining D-optimal designs for multiresponse pharmacokinetic-pharmacodynamic (PKPD) experiments where data on each response variable can be collected at different times. Most previous multiresponse model optimal design applications have considered the case where all response variables are measured at the same time points. However in practice it may not be possible to have all responses measured at the same sampling times. We propose an optimal design method to take into account the unbalanced nature of the problem. The method developed was applied to a PKPD problem that involved describing the time course of drug plasma concentrations, heart rate and mean arterial blood pressure for both a fixed effects and mixed effects regression model. Additionally a simulation study was carried out in NONMEM for one such population optimal design problem.

The enhancing effect of synthetical borneol on the absorption of tetramethylpyrazine phosphate in mouse

The main purpose of this study was to illustrate the effect of synthetical borneol (SB) on the plasma and brain concentration profile of tetramethylpyrazine phosphate (TMPP) in mice after oral administration of TMPP without or with different amounts of SB. The concentrations of TMPP on the plasma and brain in mice were determined by GC-FID. The pharmacokinetic parameters were computed by software program 3p97. Our data showed that after oral administration of 15, 30, 90 mg kg −1 of SB, oral bioavailability of TMPP in plasma was 1.52, 2.21, 2.95 times increase, respectively, than that without SB, and 1.12, 1.62, 1.93 times increase, respectively, in brain tissue. The pharmacokinetic data were simulated by non-linear least squares. The results showed that both open two-compartment model and one-order absorption were fitted to TMPP plasma and brain concentration-time course in vivo in mice. The MRT of TMPP showed same results under the conditions without or with SB. SB did enhance the oral absorption of TMPP and the concentration of TMPP in brain tissue, especially in the early period. But the use of SB did not change the behavior in vivo of TMPP.

Rapid determination of platinum plasma concentrations of chemotherapy patients using total reflection X-ray fluorescence

A fast and simple method using Total Reflection X-ray Fluorescence has been developed for the determination of platinum plasma concentrations of patients undergoing chemotherapy with Pt-bearing drugs. Avoiding chemical digestion, micro liter amounts of blood plasma are employed using Compton peak standardization and the use of matrix-matched spiked samples with known amounts of platinum for spectrometer sensitivity determination. The analytical results with the proposed procedure are compared to values obtained with Graphite Furnace Atomic Absorption Spectrometry obtaining values of comparable accuracy and precision. Measurements of the time course of the Pt plasma concentration in single-dose treatments, and of the achieved plasma concentration of multiple infusion treatments demonstrate the potential usefulness of the method for pharmacokinetic studies or for routine optimization of Pt chemotherapy treatments.

Results of a Phase I trial of sorafenib (BAY 43-9006) in combination with doxorubicin in patients with refractory solid tumors

Sorafenib (BAY 43-9006), a novel, oral multi-kinase inhibitor, blocks serine/threonine and receptor tyrosine kinases in the tumor and vasculature. Sorafenib demonstrated single-agent activity in Phase I studies, and was tolerated and inhibited tumor growth in combination with doxorubicin in preclinical studies. This Phase I dose-escalation study determined the safety, pharmacokinetics and efficacy of sorafenib plus doxorubicin. Thirty-four patients with refractory, solid tumors received doxorubicin 60 mg/m(2) on Day 1 of 3-week cycles, and oral sorafenib from Day 4 of Cycle 1 at 100, 200 or 400 mg bid. Common drug-related adverse events were neutropenia (56%), hand-foot skin reaction (44%), stomatitis (32%), and diarrhea (32%). The maximum tolerated dose was not reached. One patient with pleural mesothelioma achieved a partial response (modified WHO criteria) and remained on therapy for 39.7 weeks. Fifteen patients (48%) achieved stable disease for >/=12 weeks. Doxorubicin exposure increased moderately with sorafenib 400 mg bid. The pharmacokinetics of sorafenib and doxorubicinol were not affected. Sorafenib 400 mg bid plus doxorubicin 60 mg/m(2) was well tolerated. The increased doxorubicin exposure with sorafenib 400 mg bid did not result in significantly increased toxicity; low patient numbers make the clinical significance of this unclear. These promising efficacy results justify further clinical investigation.

Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites

In vitro experiments suggest that circulating metabolites of oxycodone are opioid receptor agonists. Clinical and animal studies to date have failed to demonstrate a significant contribution of the O-demethylated metabolite oxymorphone toward the clinical effects of the parent drug, but the role of other putative circulating active metabolites in oxycodone pharmacodynamics remains to be examined. Pharmacokinetics and pharmacodynamics of oxycodone were investigated in healthy human volunteers; measurements included the time course of plasma concentrations and urinary excretion of metabolites derived from N-demethylation, O-demethylation, and 6-keto-reduction, along with the time course of miosis and subjective opioid side effects. The contribution of circulating metabolites to oxycodone pharmacodynamics was analyzed by pharmacokinetic-pharmacodynamic modeling. The human study was complemented by in vitro measurements of opioid receptor binding and activation studies, as well as in vivo studies of the brain distribution of oxycodone and its metabolites in rats. Urinary metabolites derived from cytochrome P450 (CYP) 3A-mediated N-demethylation of oxycodone (noroxycodone, noroxymorphone, and alpha- and beta-noroxycodol) accounted for 45% +/- 21% of the dose, whereas CYP2D6-mediated O-demethylation (oxymorphone and alpha- and beta-oxymorphol) and 6-keto-reduction (alpha- and beta-oxycodol) accounted for 11% +/- 6% and 8% +/- 6% of the dose, respectively. Noroxycodone and noroxymorphone were the major metabolites in circulation with elimination half-lives longer than that of oxycodone, but their uptake into the rat brain was significantly lower compared with that of the parent drug. Pharmacokinetic-pharmacodynamic modeling indicated that the time course of pupil constriction is fully explained by the plasma concentration of the parent drug, oxycodone, alone. The metabolites do not contribute to the central effects, either because of their low potency or low abundance in circulation or as a result of their poor uptake into the brain. CYP3A-mediated N-demethylation is the principal metabolic pathway of oxycodone in humans. The central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites.

(753): Single-dose and repetitive-dose bicifadine pharmacokinetics in healthy adult male human subjects

Bicifadine is a novel non-opioid analgesic whose neurochemical actions involve the modulation of monoaminergic neurotransmitters pathways involved in pain. The compound has shown activity in chronic back pain and in acute nociceptive pain. Pharmacokinetic profiles of bicifadine and its lactam metabolite have been studied in healthy adult male human subjects following single doses of 200mg and 400mg and during multiple dose regimens of 200mg BID, 200mg TID, and 400mg BID for 8 days (10 per dose group). Plasma concentration time course data were collected over a 24-hour period following single-doses and across dosing intervals on Days 1, 4, and 8 during repetitive dosing. Pharmacokinetic metrics were estimated following noncompartmental data analysis. Peak exposures (Cmax) were achieved at a tmax of approximately 1.5 to 1.8h following single-doses and 1.8 to 2.2h during repetitive dosing. Plasma concentrations increased in a linear manner across the 200mg and 400mg single doses. Linearity was further evidenced by relatively constant apparent oral clearance and mean residence times across doses. Repetitive dosing for 8 days resulted in accumulation ratios [R] of approximately 1.2 for BID dosing and 1.8 for TID dosing. Substantial increases in volume of distribution between the 200mg (V/F= 185 & 182L) and 400mg (V/F= 280L) were observed but not readily explained. Apparent terminal half-life (t1/2) values across single doses (t1/2= 2.6 & 3.4h at 200mg; t1/2= 4.6h at 400mg) were within the limits of variability. Overall, the pharmacokinetic profile of bicifadine was well behaved and inter-individual variability was modest. Steady-state is clearly established within 4 days of BID or TID dosing. Profiles of the lactam metabolite followed a similar trend. Bicifadine is a novel non-opioid analgesic whose neurochemical actions involve the modulation of monoaminergic neurotransmitters pathways involved in pain. The compound has shown activity in chronic back pain and in acute nociceptive pain. Pharmacokinetic profiles of bicifadine and its lactam metabolite have been studied in healthy adult male human subjects following single doses of 200mg and 400mg and during multiple dose regimens of 200mg BID, 200mg TID, and 400mg BID for 8 days (10 per dose group). Plasma concentration time course data were collected over a 24-hour period following single-doses and across dosing intervals on Days 1, 4, and 8 during repetitive dosing. Pharmacokinetic metrics were estimated following noncompartmental data analysis. Peak exposures (Cmax) were achieved at a tmax of approximately 1.5 to 1.8h following single-doses and 1.8 to 2.2h during repetitive dosing. Plasma concentrations increased in a linear manner across the 200mg and 400mg single doses. Linearity was further evidenced by relatively constant apparent oral clearance and mean residence times across doses. Repetitive dosing for 8 days resulted in accumulation ratios [R] of approximately 1.2 for BID dosing and 1.8 for TID dosing. Substantial increases in volume of distribution between the 200mg (V/F= 185 & 182L) and 400mg (V/F= 280L) were observed but not readily explained. Apparent terminal half-life (t1/2) values across single doses (t1/2= 2.6 & 3.4h at 200mg; t1/2= 4.6h at 400mg) were within the limits of variability. Overall, the pharmacokinetic profile of bicifadine was well behaved and inter-individual variability was modest. Steady-state is clearly established within 4 days of BID or TID dosing. Profiles of the lactam metabolite followed a similar trend.

Sensitive determination of 4‐(4‐chlorophenyl)‐4‐hydroxypiperidine, a metabolite of haloperidol, in a rat biological sample by HPLC with fluorescence detection after pre‐column derivatization using 4‐fluoro‐7‐nitro‐2,1,3‐benzoxadiazole

4-(4-Chlorophenyl)-4-hydroxypiperidine (CPHP), one of the metabolites of haloperidol, is considered to exhibit brain toxicity. CPHP concentrations in plasma and tissue homogenates (each 200 microL) from rats were analyzed by HPLC fluorescence detection after pre-column derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). After basic extraction of the samples with benzene, the derivatization with NBD-F was conducted in borate buffer (pH 8.0) at 60 degrees C for 3 min. Mexiletine was carried through the procedure as an internal standard. The regression equation for CPHP showed a good linearity in the range of 0.03-1 microg/mL with a detection limit of 0.008 microg/mL. The coefficient of variation was less than 11.6%. Plasma concentration-time courses of CPHP after intraperitoneal or per oral administration of CPHP, haloperidol or reduced haloperidol were examined, and the pharmacokinetic parameters were estimated. Additionally, CPHP levels in various tissues at 8 h after intraperitoneal administration of these compounds were compared. The method was simple and sensitive, useful for determination of CPHP in rat biological samples using as little as 200 microL of sample volume and could be applied for pharmacokinetic study.

Population Pharmacokinetics of Pranlukast Hydrate Dry Syrup in Children with Allergic Rhinitis and Bronchial Asthma

This study aimed to assess the steady-state pharmacokinetics of pranlukast, a leukotriene receptor antagonist, in children with allergic rhinitis and bronchial asthma, and to clarify factors affecting apparent clearance (CL/F). A total of 192 plasma samples were obtained from 98 children (rhinitis 64, asthma 13, complications 21), aged 3-14 years in 2 clinical trials. Plasma concentration of pranlukast was determined by liquid chromatography connected with a tandem mass spectrometer and analyzed by a population approach using NONMEM program. The plasma concentration-time course of pranlukast was described by using a one-compartment model with the first-order absorption and lag time. The robustness of the population pharmacokinetic model was evaluated by using 200 bootstrap samples. The results of population pharmacokinetic analysis showed that only age was a factor affecting the CL/F per body weight, with CL/F decreasing with increasing age. No significant variation was seen in the CL/F between rhinitis and asthma. The interindividual variability in the CL/F and the residual variability were 19.7% and 48.4%, respectively. All the parameters fell within 10% of the bootstrapped mean. In conclusion, the results show that age is the most influential factor for explaining interindividual variability in CL/F, and the difference in diseases does not affect CL/F.

Pentosidine and Its Deposition in Renal Tissue in Renal Transplantation

Background Advanced glycation end products (AGEs) accumulate in lesions of arteriosclerosis, Alzheimer’s disease, rheumatoid arthritis, diabetic retinopathy, and diabetic nephropathy. Among AGEs, chemical quantification and immunohistologic methods for pentosidine have been established. Free pentosidine—eliminated by renal excretion— is mainly affected by renal function. In this study, we measured concentrations of plasma free and total pentosidine and immunohistologically investigated kidney graft biopsy specimens in patients after renal transplantation to investigate the renal function, plasma free and total pentosidine, and its relationship with deposition in the renal tissue. Patients and methods In 28 patients who underwent renal transplantation from 1996 to 2003, we measured the time course of plasma concentrations of free pentosidine, total pentosidine, and serum creatinine starting right after renal transplantation. Thirty-four graft biopsy specimens were immunohistologically investigated using anti-pentosidine antibody. Plasma free and total pentosidine, and serum creatinine were measured at the same time. Results Plasma free and total pentosidine were positively correlated with serum creatinine. Plasma free pentosidine and serum creatinine reached nadir values on day 34.2 ± 14.2, when the blood concentrations were 5.1 ± 1.6 pmol/mL and 1.7 ± 0.7 mg/dL, respectively. Plasma total pentosidine reached a nadir on day 116.5 ± 39.7 when the plasma concentration was 4.0 ± 1.5 pmol/mg. We correlated the time required to reach the nadir of plasma free and total pentosidine concentrations. However, neither the concentration of plasma free nor plasma total pentosidine at nadir correlated with serum creatinine. The intensity of immunostaining with anti-pentosidine antibody in proximal tubular cells was graded as weakly positive, positive, or strongly positive. Significant differences were obtained among plasma free pentosidine values between the weakly positive and strongly positive groups. Conclusions Renal transplantation improves renal function and decreases renal excretion of free pentosidine. Accordingly, total pentosidine also decreases. However, the concentrations of plasma free and total pentosidine at nadir varied among individuals; the blood concentrations were not determined by renal function alone. It was suggested that deposition of pentosidine in proximal tubular cells was more severe among patients with higher plasma free pentosidine and serum creatinine values.

Effect of Hemodialysis on the Metabolic Clearance of 5-Fluorouracil in a Patient With End-Stage Renal Failure

A 64-year-old man on chronic hemodialysis for end-stage renal disease developed peritoneal carcinomatosis, and palliative chemotherapy with fluorouracil was started. The drug was administered (325 mg/m as IV bolus, at 2 PM) on 2 separate occasions, ie, 1 hour after dialysis and 2 days later, 49 hours after dialysis. The time course of the fluorouracil plasma concentration was determined, and the main pharmacokinetic parameters were calculated. The slope of the monoexponential decay of plasma concentration was significantly greater 1 hour (0.161 minutes) than 49 hours after dialysis (0.127 minutes), and plasma clearance was correspondingly higher (1.78 L/min versus 1.46 L/min). The volume of distribution did not change (11.1 L versus 11.5 L). Because fluorouracil is minimally excreted by the renal route (about 10% of the dose) and is almost entirely metabolized by dihydropyrimidine dehydrogenase (DPD), it is suggested that plasma factors that accumulate during the interdialytic period and are removed by dialysis may inhibit DPD activity and, consequently, fluorouracil metabolic clearance.

Systemic Nitric Oxide Production Rate during Hemodialysis and Its Relationship with Nitric Oxide-Related Factors

Background/Aims:Nitric oxide (NO) plays a key role in the regulation of vascular tone and controls both local and systemic hemodynamics. Here, we estimated systemic NO production rates of hemodialysis (HD) patients, based on the time course of plasma concentration of nitrate (an oxidative end product of NO) and investigated possible roles of NO-related factors. Methods: We measured plasma concentrations of nitrate, L-arginine (a substrate of NO synthase: NOS), asymmetric dimethylarginine (ADMA, an endogenous NOS inhibitor), tetrahydrobiopterin (BH₄, a NOS cofactor), dihydrobiopterin (BH₂, an oxidized form of BH₄) and oxidized low-density lipoprotein (oxyLDL; an index of oxidative stress) before and after 30-min and 4-hour HD (n = 10). Results:The time-averaged NO production rate during HD was estimated by fitting the time course of plasma nitrate concentration with a single-compartment model (4.00 ± 0.82 µmol/min, 4.99 ± 1.08 µmol/kg/h). The L-arginine/ADMA ratio (L-arginine availability) after 30-min HD showed a positive correlation with the NO production rate (p < 0.05). Conclusion: The systemic NO production rate during HD could be estimated by the single-compartment analysis. The L-arginine/ADMA ratio seems to play an important role in the regulation of the NO production during HD.

A New Coenzyme Q10 Tablet-Grade Formulation (all-Q®) Is Bioequivalent to Q-Gel® and Both Have Better Bioavailability Properties than Q-SorB®

Commercial Coenzyme Q10 (CoQ10, ubiquinone) formulations are often of poor intestinal absorption. We investigated the bioavailability of DSM Nutritional Products Ltd. (Kaiseraugst, Switzerland) CoQ10 10% TG/P (all-Q), a new tablet-grade formulation, with CoQ10 Q-Gel Softsules based on the Bio-Solv technology (Tishcon Corp., Salisbury, MD; marketed by Epic4Health, Smithtown, NY) and Q-SorB (Nature's Bounty, Bohemia, NY). Twelve healthy male subjects participated in a randomized, three-period crossover bioequivalence study. Plasma CoQ10 was determined from pre-dose until +36 hours. To compare bioavailability, corrected maximum concentration (Cmax) and area under the curve from 0 to +14 hours [AUC(0-14 h)] were assessed and tested for bioequivalence. The bioequivalence ranges of 0.8-1.25 hour x microg/mL for AUC(0-14 h) and 0.75-1.33 microg/mL for Cmax were applied. In summary, the kinetic profiles of all CoQ10 preparations revealed a one-peak plasma concentration-time course. Highest Cmax values were seen after Q-Gel application, whereas time to Cmax was nearly identical across all treatments. The AUC(0-14 h) values were highest for Q-Gel, narrowly followed by all-Q. The tests for bioequivalence showed a bioequivalence between Q-Gel and all-Q, and both preparations were found to have better bioavailability properties than Q-SorB. Although all-Q and Q-Gel have equivalent bioavailability properties, all-Q can be directly used in tablets, while this is not the case for Q-Gel or other similar forms.

Once-a-Day Extended-Release Dosage form of Divalproex Sodium III: Development and Validation of a Level A in Vitro–in Vivo Correlation (IVIVC)

Defining a quantitative and reliable relationship between in vitro drug release and in vivo absorption is highly desired for rational development, optimization, and evaluation of controlled-release dosage forms and manufacturing process. During the development of a once-daily extended-release (ER) tablet of divalproex sodium, a predictive in vitro drug release method was designed and statistically evaluated using three formulations with varying release rates. In order to establish an internally and externally validated Level A IVIVC, a total of five different ER formulations of divalproex sodium were used to evaluate a linear IVIVC model based on the in vitro test method. For internal validation, a single-dose four-way crossover study (N = 16) was performed using fast-, medium-, and slow-releasing ER formulations and a 12-h IV infusion of valproic acid as reference. To validate the IVIVC externally, a second three-way crossover study (N = 36) was performed using slightly-fast-, medium-, and slightly-slow-releasing ER formulations. The in vivo absorption-time profile was inferred by deconvolution of the observed plasma concentration-time profiles against the unit disposition function (UDF). A linear IVIVC model was established in which the in vivo absorption was expressed as a function of in vitro drug release. Plasma profiles of ER formulations were estimated via convolution of in vitro release profiles with the UDF. Successful internal and external validations of the model were demonstrated by individual and average absolute percent prediction errors of </=9% for both C(max) and AUC(infinity). In conclusion, a Level A IVIVC describing the entire time-course of plasma concentrations was developed and validated, both internally and externally, for ER formulations of divalproex sodium.

Untersuchungen zur verminderten Protein-C-Expression in der schweren Sepsis

Low concentration of protein C in severe sepsis may be associated with increased morbidity and mortality. The present study was designed to clarify to what extent there are differences in the time course of plasma concentrations of protein C in patients with systemic inflammatory response syndrome or patients with severe sepsis. In addition, the cause of decreased expression of protein C in severe sepsis was examined. 32 patients with severe sepsis and 10 patients with systemic inflammatory response syndrome admitted to a surgical intensive care unit were enrolled in the study. While the patients stayed in the intensive care unit protein C plasma concentrations and the clotting factors thrombin-antithrombin-complex and factor VII were determined twice weekly. Comparing patients with severe sepsis and systemic inflammatory response syndrome there was no significant difference concerning plasma levels of protein C, thrombin-antithrombin-complex and factor VII. In contrast, surviving patients with severe sepsis exhibited significant higher protein C levels compared to non-survivors. In addition, significant lower plasma levels of thrombin-antithrombin-complex were determined in survivors compared to non-survivors. However, factor VII displayed no significant group difference. Surviving patients with severe sepsis exhibited higher plasma concentrations of protein C than patients who died during severe sepsis. The lower plasma concentrations of protein C in non-survivors may be caused by an increased turnover of protein C served as endogenous anticoagulant in sepsis associated activation of coagulation.