Absorption Phases Research Articles

AN INSIGHT INTO COLLOIDAL GAS APHRON DRAINAGE USING ELECTRICAL CONDUCTIVITY MEASUREMENT

In the present paper Electrical Conductivity (EC) of Colloidal Gas Aphron (CGA) suspensions was measured for anionic and cationic surfactants (Sodium Dodecyl Sulfate (SDS) and Tetradecyl Trimethyl Ammonium Bromide (TTAB)). Experiments were made for different concentrations of SDS (6, 8.1, 10 mM) and TTAB (2, 3.51, 5 mM). CGA drainage behavior was observed and measured using 1 liter measuring cylinder while recording EC. Studying the results, CGA drainage process was observed as four-phase mechanism, instead of three conventional phases. Regardless of surfactant concentration and type, the drainage process is divided in to absorption, macroscopic, bubble, and microscopic phases. Drainage rate did not change at the end of bubble phase, with the maximum value at the end of absorption phase. Results showed that electrical conductivity is a more sensitive property for studying CGA characterization.

Oral absorption and oxidative metabolism of atrazine in rats evaluated by physiological modeling approaches

Atrazine (ATRA) is metabolized by cytochrome P450s to the chlorinated metabolites, 2-chloro-4-ethylamino-6-amino-1,3,5-triazine (ETHYL), 2-chloro-4-amino-6-isopropylamino-1, 3, 5-triazine (ISO), and diaminochlorotriazine (DACT). Here, we develop a set of physiologically based pharmacokinetic (PBPK) models that describe the influence of oral absorption and oxidative metabolism on the blood time course curves of individual chlorotriazines (Cl-TRIs) in rat after oral dosing of ATRA. These models first incorporated in vitro metabolic parameters to describe time course plasma concentrations of DACT, ETHYL, and ISO after dosing with each compound. Parameters from each individual model were linked together into a final composite model in order to describe the time course of all 4 Cl-TRIs after ATRA dosing. Oral administration of ISO, ETHYL and ATRA produced double peaks of the compounds in plasma time courses that were described by multiple absorption phases from gut. An adequate description of the uptake and bioavailability of absorbed ATRA also required inclusion of additional oxidative metabolic clearance of ATRA to the mono-dealkylated metabolites occurring in GI a tract compartment. These complex processes regulating tissue dosimetry of atrazine and its chlorinated metabolites likely reflect limited compound solubility in the gut from dosing with an emulsion, and sequential absorption and metabolism along the GI tract at these high oral doses.

Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency

The oral loading test with tetrahydrobiopterin (BH(4)) is used to discriminate between variants of hyperphenylalaninaemia and to detect BH(4)-responsive patients. The outcome of the loading test depends on the genotype, dosage of BH(4), and BH(4) pharmacokinetics. A total of 71 patients with hyperphenylalaninaemia (mild to classic) were challenged with BH(4) (20 mg/kg) according to different protocols (1 x 20 mg or 2 x 20 mg) and blood BH(4) concentrations were measured in dried blood spots at different time points (T(0), T(2), T(4), T(8), T(12), T(24), T(32) and T(48 h)). Maximal BH(4) concentrations (median 22.69 nmol/g Hb) were measured 4 h after BH(4) administration in 63 out of 71 patients. Eight patients presented with maximal BH(4) concentrations approximately 44% higher at 8 h than at 4 h. After 24 h, BH(4) blood concentrations dropped to 11% of maximal values. This profile was similar using different protocols. The following pharmacokinetic parameters were calculated for BH(4) in blood: t (max) = 4 h, AUC (T(0-32)) = 370 nmol x h/g Hb, and t (1/2) for absorption (1.1 h), distribution (2.5 h), and elimination (46.0 h) phases. Maximal BH(4) blood concentrations were not significantly lower in non-responders and there was no correlation between blood concentrations and responsiveness. Of mild PKU patients, 97% responded to BH(4) administration, while one was found to be a non-responder. Only 10/19 patients (53%) with Phe concentrations of 600-1200 mumol/L responded to BH(4) administration, and of the patients with the severe classical phenotype (blood Phe > 1200 mumol/L) only 4 out of 17 patient responded. An additional 36 patients with mild hyperphenylalaninaemia (HPA) who underwent the combined loading test with Phe+BH(4) were all responders. Slow responders and non-responders were found in all groups of HPA.

Validation of Ink Media Interaction Mechanisms for Dye and Pigment-based Aqueous and Solvent Inks

In this article, the dynamics of droplet impingement, spreading, absorption, penetration, and evaporation are discussed for different ink jet ink classes. Both dye and pigment based aqueous inks are included, as well as solvent or eco-solvent inks. The fundamental physicochemical rules determining the dynamics can be very dependent from ink to ink, and are compared. After impact there is a fast spreading phase that takes into account the evolution of the kinetic energy of the droplet to forced spreading on the receiver. Later on, diffusion or capillary wicking is possible, and is depending upon the nature of the substrate. The speed of these processes can be influenced by the presence of dyes or pigments in the inks. After absorption / penetration, the carrier liquid can evaporate leading to the final equilibrium condition. For (eco)-solvent inks the evaporation is much more important compared to the other penetration/absorption processes, so that it cannot be easily separated into different independent time scales. In situ visualization of the dynamics for real size ink jet droplets is not easy, especially for the droplets of only a few pl volume. Comparison of large droplet impact dynamic studies with theory and extrapolation of the behavior to small droplet cases has some risks. Test experiments have been setup in order to simulate transient absorption phases on different receivers. Traditional microscopic evaluations have been done in order to verify whether the proposed models for describing the transient behavior are in agreement with the experimental observations for real small sized droplets.

Arterial and Venous Pharmacokinetics of Ropivacaine with and without Epinephrine after Thoracic Paravertebral Block

Animal and volunteer studies indicate that ropivacaine is associated with less neurologic and cardiac toxicity than bupivacaine. Ropivacaine may offer advantages when used for thoracic paravertebral block. This study was designed to describe the pharmacokinetics of ropivacaine after thoracic paravertebral block. Twenty female patients undergoing elective unilateral breast surgery were randomly assigned to receive a single bolus thoracic paravertebral injection of 2 mg/kg ropivacaine, with or without 5 mug/ml epinephrine. Simultaneous arterial and venous blood samples were obtained for plasma ropivacaine assay. Data were analyzed with NONMEM, using two possible absorption models: conventional first-order absorption and absorption following the inverse gaussian density function. Epinephrine reduced the peak plasma concentrations and delayed the time of peak concentration of ropivacaine in both the arterial and venous blood. The time course of drug input into the systemic circulation was best described by two inverse gaussian density functions. The median bioavailability of the rapid component was approximately 20% higher when epinephrine was not used. The mean absorption times were 7.8 min for the rapid absorption phase and 697 min for the slow absorption phase, with wide dispersion of the absorption function for the acute phase. The half-time of arterial-venous equilibration was 1.5 min. The absorption of ropivacaine after thoracic paravertebral block is described by rapid and slow absorption phases. The rapid phase approximates the speed of intravenous administration and accounts for nearly half of ropivacaine absorption. The addition of 5 mug/ml epinephrine to ropivacaine significantly delays its systemic absorption and reduces the peak plasma concentration.

Sex-related differences in the pharmacokinetics of oral ciprofloxacin.

The oral pharmacokinetics of ciprofloxacin were studied in healthy volunteers to assess the influence of sex on its disposition. Subjects (8 males, 7 females) received a single oral dose of ciprofloxacin 750 mg, blood and urine samples were collected, and ciprofloxacin concentrations were determined. A two-compartment open-model with two or three absorption phases, each one having a fitted independent lag time, best fit the data using a weighted least squares estimator. Univariate and multivariate regression analyses were performed to determine the influence of renal function, weight, and subject sex on the oral clearance (CL(S)/F) and apparent steady-state volume of distribution (V(ss)/F) of ciprofloxacin. Females had a median C(max) of ciprofloxacin that was 30% greater than males and a significantly smaller median (range) V(ss)/F: 81.1 (44.8-111.6) versus 170.9 (140.9-213.4), respectively (p < 0.01). In addition, females had increased exposure to ciprofloxacin, with a slower median (range) CL(S)/F of 28.3 L/h (24.5-33.4) compared to 44.4 L/h (41.4-53.7) for males (p < 0.01). Regression analyses revealed that subject sex was the only significant predictor of CL(S)/F (p < 0.001), but both body weight (p = 0.04) and subject sex (p < 0.005) were significant predictors of V(ss)/F. Fixed oral doses of ciprofloxacin will lead to higher maximum concentration and total drug exposure in females compared to males and do not appear to be solely related to weight-based differences.

Epitopes corresponding to the envelope genetic subtype are present on the surface of free virions of HIV-1 group M primary isolates and can be detected in neutralization assays with extended incubation phases.

The hypothesis is that there are neutralizing epitopes on the surface of free virions of human immunodeficiency virus type 1 (HIV-1) that correspond to the genetic subtype of the envelope glycoprotein. Assays with extended incubation and reduced absorption phases are required to demonstrate neutralization with antibodies to these epitopes. These assays quantify virus infectivity, rather than reductions in release of antigen into culture supernatants. Neutralizing antibodies reduce virus infectivity by at least 80%, as scored by the presence/absence of antigen released after 14 days in culture of mitogen-transformed peripheral blood mononuclear cells (PBMCs). The epitopes are shared within different subtypes of group M, but not group O, isolates. Individual plasma, selected from three, independent panels of seropositive individuals, cross-neutralize within each subtype as well as the combinations of A with C, B with D or G, and C with CRF01_AE. Isolates within subtype B show the greatest variation in their resistance to neutralization, ranging from highly sensitive to highly resistant. No highly sensitive subtype D isolates were identified. Isolates from subtypes A, C, and CRF01_AE were all resistant. The strategic implication for vaccine design is that antibodies to a limited number of epitopes can neutralize more than 90% of the HIV-1 isolates that are circulating currently in the world. Also, since only antibodies that produce an all-or-nothing loss in virus infectivity can reasonably be expected to prevent the viremic phase after in vivo infection, assays with extended incubation, and culture phases should be used to monitor current efficacy trials.

The vagus is inhibitory of the late postprandial insulin secretion in conscious pigs

The vagus is involved in the cephalic phase of insulin secretion but its role in the meal absorption phase of insulin release remains to be defined. The aim of this study was therefore to evaluate the role of the vagus in the early and the late meal absorption phases of insulin secretion. In six pigs, venous insulin profiles were compared in intact animals, after ventral or dorsal vagal trunk section, and after section of both vagal trunks (truncal vagotomy). Since gastric emptying could be modified by vagotomy, it was recorded concomitantly by gamma scintigraphy. Semi-solid (porridge) and liquid (glucose 10%) meals were tested. Truncal vagotomy significantly increased insulin release compare to intact animals after glucose (63.8%) and porridge (174.4%) meals in the early and the late absorption phases of insulin secretion, respectively. For the glucose meal, this effect could be explained by a vagally mediated change in gastric emptying rate, since insulin concentrations for a similar amount of nutrient propelled to the duodenum were not different in intact and truncal vagotomized animals. In contrast, after the porridge meal, truncal vagotomy was associated with a second, later occurring increase in circulating insulin, which could not be explained by changes in gastric emptying rate. These results demonstrate for the first time an inhibitory role of the vagus in the late meal absorption phase of insulin release.

A ortodoxia neoclássica

NO ARTIGO enfoca-se a difusão da teoria neoclássica na formação dos economistas brasileiros. Com essa finalidade, apresenta-se de início uma caracterização sumária dessa concepção teórica, que é amplamente dominante em Economia, em quase todo mundo. Em seqüência, faz-se uma análise desse processo com base em resultados de outros autores que examinaram a evolução dos cursos de pós-graduação no Brasil e em pesquisa empírica sobre os fundamentos teóricos dos artigos publicados na Revista Brasileira de Economia e na revista Estudos Econômicos. Nas conclusões, mostra-se que essa difusão já ultrapassou as fases de absorção e de consolidação, tendo entrado agora numa fase caracterizada pela ênfase na integração internacional.

Pharmacokinetics of Abacavir in HIV-1-Infected Patients with Impaired Renal Function

Background: Abacavir is a potent, novel 2′-deoxyguanosine analogue reverse transcriptase inhibitor (NRTI) which effectively suppresses HIV-1 replication. To date, there is no pharmacokinetic study in patients with renal impairment. Methods: Five HIV-1-infected patients with various degrees of renal dysfunction (creatinine clearance 60, 40, 25, 20 and 1 haemodialyzed patient) were evaluated after being treated for at least 2 months with multi-antiretroviral therapy including abacavir. After an overnight fast, the subjects received their abacavir dosage (600 or 300 mg). Blood samples were withdrawn and plasma concentrations determined. A nonparametric pharmacokinetic analysis was then performed. The dialysability of abacavir was also evaluated. Results: Time of maximum plasma concentration (T_max) was constant among the subjects with a mean value of 0.7 ± 0.27 h (range 0.33–1). Maximum plasma concentration (C_max) ranged from 2.76 to 4.15 mg/l (mean 3.44 ± 0.59). The elimination half-life ranged from 1.31 to 2.67 h (mean 2.08 ± 0.51). Normalized C_max/dose ranged from 0.007 to 0.014 mg/l and normalized AUC(0-inf)/dose ranged from 0.014 to 0.035 mg·h/l. In haemodialysis the dialysance was 60–80 ml/min with a fractional drug removal of 24% during a 4-hour haemodialysis session with a high permeability membrane. Discussion: In our patients, absorption, elimination and distribution phases were not altered by renal insufficiency. Furthermore, our pharmacokinetic data are similar to those obtained in patients with normal renal function. Therefore, dosage adjustment is not necessary in patients with renal insufficiency. In haemodialyzed patients, treatment can be administered independently to the dialysis session because of the negligible elimination of abacavir in the dialysate.

Arteether toxicokinetics and pharmacokinetics in rats after 25 mg/kg/day single and multiple doses

Multiple doses of arteether (ARTE) at 25 mg/kg cause CNS and anorectic toxicities in rats. The same dose of ARTE was used to study the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) following single administration. Animals were administered ARTE in sesame oil for 7 days, blood samples were collected using destructive sampling for up to 192 h after dosing and assayed by HPLC-ECD. Two other groups of rats were administered either a single 25 mg/kg i.v. or i.m. dose. In addition, the drug remaining in the i.m. injection site was measured. During the 7 day treatments, anorectic toxicity of ARTE was observed, and that caused significant reductions in food consumption and body weight after day 2. TK data on days 2-7 revealed marked changes compared to the PK parameters estimated on day 1. AUC (4367 ng x h/ml) on day 7 was 5-fold higher than AUC (905 ng x h/ml) on day 1. The volume of distribution at steady state (V(SS)) on day 7 (41.8 l) was 40% of the day 1 value of the V(SS) (104.3 l). Clearance (CL) was increased by 89% of the day 1 value, from 0.98 l/h to 1.85 l/h on day 7. The elimination t(1/2) of ARTE was also prolonged from 13.7 h (day 1) to 31.2 h (day 7). These data suggest that ARTE may have altered its distribution and elimination in rats as a result of the systemic toxicity. Analysis of the injection sites showed that 38% and 91% of the total amount of ARTE single dose remained in the muscles at 24 h (after first injection) and 168 h (at 24 h after 7 daily multiple doses), respectively. Fast and slow absorption phases from muscle were seen with t(1/2) of 0.97 h and 26.3 h, respectively. The apparent elimination t(1/2) of ARTE after i.m. injection (13.7 h) was much longer than that after i.v. dosing (0.67 h) due to the prolonged muscle absorption phase. Acute toxicity data of artemisinin drugs demonstrated that animals receiving a high single ARTE dose in sesame oil died between days 5-11, similar to artemether. When animals received dihydroartemisinin formulated in 50% DMAC/oil, or artesunic acid and artelinic acid in 0.9% saline vehicle, they died between days 1 and 2. This suggests that delayed onset toxicity and death in the ARTE rats may also be due to slow absorption and prolonged drug exposure. Therefore multiple i.m. administrations cause anorexia and drug accumulation, possibly affecting the toxicokinetics and efficacy of the drug.

Bioavailability of norethisterone acetate alone and in combination with estradiol administered in single or multiple oral doses to postmenopausal women

Objectives: Twenty-four postmenopausal women were randomly allocated to a cross-over trial for an investigation of the pharmacokinetics of norethisterone acetate (NETA; 0.5 mg), administered alone or in combination with estradiol (E2; 1 mg), both after a single oral dose. In a second trial, the above combination of 0.5 mg NETA with 1 mg E2 was administered daily for 28 days. Methods: Plasma levels of NET, E2, estrone (E1) and estrone sulphate fraction containing an admixture of estrone glucuronide (E1S/E1G) were measured by radioimmunoassay at various intervals up to 72 h in the first trial and at the same intervals after the 28th day in the second trial. Results: In the first, single-dose trial, pharmacokinetic parameters of NET were similar for NETA administered alone and its combination with E2. There was no statistically significant difference in the area under curve values AUC 0–24 and AUC 0–∞ and no apparent major differences were observed for other pharmacokinetic parameters. No carry-over effects due to the cross-over design were seen. The multiple dosage in the second trial did not cause any major changes in the pharmacokinetic parameters of NET, except for the AUC 0–24 and AUC 0–∞ values which were significantly higher than those seen in the first trial. The levels of E2 exhibited, shortly after the intake of E2, a rapid burst. The levels gradually decreased to a nadir followed by an increase to the main peak and by the subsequent elimination phase. The difference between the peak and nadir levels was significant ( P<0.05) in the second, multiple-dose trial. This bimodal pattern was not observed in earlier studies. The main metabolite of E2 was E1S/E1G, followed by E1, as could be seen from the AUC 0–∞ values. These were, in both trials, ≈300 and 7-times higher for the E1S/E1G and E1, respectively, than those for E2. For all analytes, the AUC 0–24 values were significantly higher in the second trial than those found in the first trial, indicating accumulation upon repeated administration. Pharmacokinetics of all analytes remained linear in the second trial, as follows from the statistically established equality of AUC 0–24 found in the second, multiple-dose trial with AUC 0–∞ in the first, single-dose trial. The absorption half-life and t-max values of E1S/E1G appeared to be considerably shorter than those of E1 in both trials. Conclusions: The bioavailability of NET was not influenced by its combination with 1 mg E2. The most abundant metabolite of E2 was the E1S/E1G fraction, which may have served as the main source of E2 and other estrogens due to metabolic interconversions during the absorption and elimination phases.

Pegylated liposomal doxorubicin (DOXIL®, CAELYX®) distribution in tumour models observed with confocal laser scanning microscopy

The activity of doxorubicin hydrochloride in preclinical tumor models is markedly improved by encapsulation in pegylated liposomes (DOXIL, CAELYX). To understand this response in better detail, spatial and temporal drug distribution in frozen tumor sections was observed with confocal laser scanning (CLS) microscopy. Tumor tissue absorption and distribution phases were markedly altered by pegylated liposome encapsulation. The resultant tumor tissue area under the curve was increased at least several fold over an equivalent dose of free drug. The majority of visible fluorescence was in the nuclear compartment; encapsulated drug apparently leaves liposomes in the interstitial spaces within minutes and appears in the nucleus. Pilot experiments suggest that drug and lipid uncouple at an extracellular location. The increased nuclear exposure to drug is likely responsible for the enhanced therapeutic effect of encapsulation in pegylated liposomes.

Pressure DSC studies on the formation and reproducibility of double peaks in the sorption of LaNi5-H2 during thermal cycling

Abstract Pressure Differential Scanning Calorimetry (PDSC) has been used to study the conditions of formation and disappearance of double peaks in the absorption and desorption of the LaNi5-H2 system during thermal cycling. Thermal absorption-desorption cycling reveals double-peak formation both in absorption and desorption phases. Splitting of a single peak into a double-one is induced below 60°C even in case of absorption. The double peak disappears, due to annealing at moderate temperatures in a hydrogen atmosphere, easier in absorption than in desorption. It reappears, however, easily when thermal cycling is continued.

Population pharmacokinetics of sirolimus in kidney transplant patients.

To characterize the dose-related pharmacokinetics of the immunosuppressant agent sirolimus (formerly rapamycin) in kidney transplant patients by use of two-stage and nonlinear mixed-effect model population methods. Patients (n = 36) from three centers (Germany, the United Kingdom, and Sweden) who received steady-state oral doses of cyclosporine (ciclosporin) were assessed after single oral administration of sirolimus at doses of 3, 5, 10, and 15 mg/m2. Plasma and whole blood sirolimus samples were analyzed by a high-performance liquid chromatographic/mass spectrophotometric method. Simultaneous fitting used biexponential functions with intercept/slope or clearance/volume terms, as well as first-order absorption (ka) and a lag-time. The nonlinear mixed-effect model method (P-Pharm) provided a better characterization of sirolimus kinetics, especially for the absorption and distribution phases where fewer data were available per patient. Sirolimus distribution between whole blood and plasma was concentration-independent, with a mean blood/plasma ratio (coefficient of variation) of 30.9 (48.5%). Elimination was not influenced by dose, as shown by estimates of the terminal half-life of 63 hours (27.5%) and apparent oral blood clearance of 8.9 L/hr (38.2%). Sirolimus distribution parameters were influenced by body weight and surface area. Sirolimus was rapidly absorbed, as shown by the absorption lag-time of 0.27 hour (35.1%), and ka of 2.77 hr-1 (48.4%). The concomitant administration of sirolimus and cyclosporine did not reveal any pharmacokinetic interactions. This report provides an initial population pharmacokinetics of sirolimus in kidney transplant recipients receiving cyclosporine concurrently. Sirolimus blood and plasma pharmacokinetics were biexponential and linear for doses from 3 to 15 mg/m2. No pharmacokinetic interaction was found between sirolimus and cyclosporine.

Effect of Temperature on the Drying Rate of Gin Run Cotton Seed

Moisture control during the harvesting, storage, and processing phases of cotton production is essential for producing a quality product. Basic information relating environmental parameters to equilibrium moisture content and the moisture transfer rates for cotton and its component parts will lead to a better understanding of the processes involved and design and control criteria for cotton conditioning equipment. This report depicts the moisture desorption rates for gin run cotton seed. Absorption values are shown for temperatures of 20 and 35C and desorption values for temperatures ranging from 20 to 130C (68-266F). The desorption (drying) moisture data were plotted against time and found to be exponential in nature. Nonlinear regression analysis was used to fit the value of the coefficients in the theoretical falling rate equation to the experimental data. The desorption (drying) data fit the theoretical falling rate (exponential decay) function reasonably well, especially at temperatures above 100C. Temperature significantly affected the coefficient containing the diffusivity parameter in the nonlinear equations. A generalized solution of the falling rate equation was developed as a function of absolute temperature, which should be suitable for engineering calculations. Results indicate that moisture absorption by cotton seed undergoes two absorption phases. The first absorption phases appears to be physical in nature and approximates the curves of other biological materials. The second phase, which shows an increased moisture absorption rate after a leveling off period, may indicate increased metabolic activity.

Therapeutic drug monitoring principles in the neonate

Therapeutic drug monitoring in the newborn infant is necessary because dose requirements differ greatly from those for older children. These differences stem from major changes in kinetic disposition at the absorption, distribution, and elimination phases. The small blood volume of neonates makes them sensitive to iatrogenic blood loss. Similarly, the small size of these patients means that medication errors frequently lead to morbidity and even mortality. The clinical laboratory must set up strict, high-standard, carefully updated guidelines to ensure the safety of infants who need drug therapy at this very vulnerable phase of their lives.

Biphasic drug absorption from the epidural space of the dog may limit the utility of a slow release medium molecular weight hyaluronic acid-lidocaine ionic complex formulation.

Previous epidural studies conducted in rabbits have described a viscous lidocaine-hyaluronate formulation (L-HA) that prolonged the duration of sensory blockade twofold and decreased the rate of drug absorption fourfold relative to a solution formulation. As further evaluation of the L-HA formulation required studies in a larger animal that more closely reflected the characteristic absorption kinetics observed in humans, a conscious dog model was used to functionally and kinetically evaluate the viscous formulation relative to lidocaine solution. In terms of the measured pharmacodynamic end point (loss of weight-bearing ability in hind legs), epidural administration of the L-HA formulation did not prolong the duration of action relative to lidocaine solution in spite of a markedly altered pharmacokinetic profile. For example, administration of L-HA reduced the mean plasma lidocaine Cmax value approximately 50% and increased the Tmax value approximately fivefold relative to lidocaine solution. However, the viscous L-HA formulation did cause a significant prolongation in the latency of onset (P < 0.001) relative to lidocaine solution. The dog exhibited "flip-flop" pharmacokinetics and absorption was biphasic after epidural administration of lidocaine solution (apparent t1/2 of the fast and slow absorption phases were 4 min and 131 min, respectively). The L-HA formulation markedly altered the absorption kinetics such that a single, slow absorption phase was evident (apparent t1/2 of 56 min), although this rate was more rapid than the slow phase observed after lidocaine solution. It is possible that the inability of the hyaluronate-based formulation to further reduce the magnitude of the slow absorption phase resulted in the failure to prolong the duration of action. These data highlight the need to carefully consider the absorption kinetics and pharmacokinetic characteristics of the animal models chosen to evaluate new formulation of epidurally administered local anesthetics.

Biphasic Drug Absorption from the Epidural Space of the Dog May Limit the Utility of a Slow Release Medium Molecular Weight Hyaluronic Acid-Lidocaine Ionic Complex Formulation

Previous epidural studies conducted in rabbits have described a viscous lidocaine-hyaluronate formulation (L-HA) that prolonged the duration of sensory blockade twofold and decreased the rate of drug absorption fourfold relative to a solution formulation. As further evaluation of the L-HA formulation required studies in a larger animal that more closely reflected the characteristic absorption kinetics observed in humans, a conscious dog model was used to functionally and kinetically evaluate the viscous formulation relative to lidocaine solution. In terms of the measured pharmacodynamic end point (loss of weight-bearing ability in hind legs), epidural administration of the L-HA formulation did not prolong the duration of action relative to lidocaine solution in spite of a markedly altered pharmacokinetic profile. For example, administration of L-HA reduced the mean plasma lidocaine Cmax value approximately 50% and increased the Tmax value approximately fivefold relative to lidocaine solution. However, the viscous L-HA formulation did cause a significant prolongation in the latency of onset (P < 0.001) relative to lidocaine solution. The dog exhibited "flip-flop" pharmacokinetics and absorption was biphasic after epidural administration of lidocaine solution (apparent t1/2 of the fast and slow absorption phases were 4 min and 131 min, respectively). The L-HA formulation markedly altered the absorption kinetics such that a single, slow absorption phase was evident (apparent t1/2 of 56 min), although this rate was more rapid than the slow phase observed after lidocaine solution. It is possible that the inability of the hyaluronate-based formulation to further reduce the magnitude of the slow absorption phase resulted in the failure to prolong the duration of action. These data highlight the need to carefully consider the absorption kinetics and pharmacokinetic characteristics of the animal models chosen to evaluate new formulations of epidurally administered local anesthetics. (Anesth Analg 1996;83:1244-50)

Discontinuous oral absorption pharmacokinetic model and bioavailability of 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU) in rats.

1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU), the L isomer of FMAU, has shown potent activity against hepatitis B virus and Epstein-Barr virus. L-FMAU showed double peaks in the plasma concentration versus time profiles following oral administration to rats, indicating discontinuous oral absorption. The objective of this study was to characterize the bioavailability and pattern of L-FMAU absorption using a pharmacokinetic model which incorporated two separate absorption processes following oral administration of the nucleoside in an animal model, the rat. Simultaneous fitting of differential equations to L-FMAU plasma concentrations following oral and intravenous administration was performed using PCNONLIN. Total clearance of L-FMAU was moderate, averaging 0.47 +/- 0.16 L h-1 (mean +/- SD). Distributional clearance averaged 0.18 +/- 0.14 L h-1. The volume of the central compartment averaged 0.30 +/- 0.09 L, and the volume of the peripheral compartment averaged 0.15 +/- 0.08 L. The first-order absorption rate constants describing the first and second absorption phases averaged 1.22 +/- 1.56 and 4.14 +/- 5.42 h-1, respectively. Oral bioavailability was calculated by three methods: AUC, urinary excretion data, and a discontinuous oral absorption pharmacokinetic model. Bioavailability averaged 0.59 +/- 0.16, 0.64 +/- 0.23, and 0.63 +/- 0.13, respectively, for the three methods. The discontinuous oral absorption pharmacokinetic model is a promising new method for estimating absorption from two phases and for calculating oral bioavailability.