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Thiamphenicol (TP) pharmacokinetics were studied in Japanese quails (Coturnix japonica) following a single intravenous (IV) and oral (PO) administration at 30 mg/kg BW. Concentrations of TP were determined with HPLC and were analyzed by a noncompartmental method. After IV injection, elimination half-life (t1/2λz ), total body clearance (Cltot ) volume of distribution at steady state (Vdss ), and mean residence time (MRT) of TP were 3.83 hr, 0.19 L/hr/kg, 0.84 L/kg, and 4.37 hr, respectively. After oral administration of TP, the peak plasma concentration (Cmax ) was 19.81 μg/ml and was obtained at 2.00 hr (tmax ) postadministration. Elimination half-life (t1/2λz ) and mean absorption time (MAT) were 4.01 hr and 1.56 hr, respectively. The systemic bioavailability following oral administration of TP was 78.10%. TP therapy with an oral dosage of 30 mg/kg BW is suggested for a beneficial clinical effect in quails.

Pharmacokinetics of difloxacin (DF), a fluoroquinolone antibiotic, were investigated in Japanese quails (Coturnix japonica) after a single intravenous (IV) and oral (PO) administration of 10 mg/kg bodyweight. Plasma concentration profiles of DF were analyzed by a compartmental pharmacokinetic method. Following IV injection, the plasma concentration vs time profile was best described by a two-compartment open model. Elimination half-life (t1/2β), total body clearance (Cltot), volume of distribution at steady state (Vdss) and mean residence time (MRT) of DF were 5.45 ± 0.14 h, 0.22 ± 0.01 L/kg/h, 1.54 ± 0.06 L/kg and 6.92 ± 0.19 h, respectively. Following PO administration, DF was rapidly absorbed, with peak plasma concentration (Cmax) of 3.67 μg/mL attained at 1.90 h (Tmax) after administration. Absorption half-life (t1/2ab), elimination half-life (t1/2el), mean absorption time (MAT) were 0.5 h, 5.26 h and 1.11 h, respectively. The bioavailability (F) following PO administration of DF was high (84.40%). For a successful clinical effect of DF in quails, a multiple dosage regimen of 10 mg/kg bodyweight, administered orally every 24 h is recommended to maintain effective plasma concentrations with bacterial infections, in which MIC90 is

1-Aminobenzotriazole (ABT) is a mechanism-based inactivator of major cytochrome P450 (CYP) enzymes, which is used in multiple mechanistic studies. The purpose was to evaluate the effect of 2 and 16-h pretreatment regimens of ABT on the exposures of triazolam in rat. Another objective was to evaluate the effect of ABT on gastric emptying of acetaminophen. Plasma area under the curve (AUC) of triazolam was increased by 101-fold and 81-fold for the rats pretreated with ABT at 2 and 16 h, respectively, compared to control rats. Time to reach maximum concentration was 0.3, 4.8 and 3.7 h in control, 2 and 16-h pretreatment animals, respectively. In the case of acetaminophen, where Tmax was not delayed, the mean absorption time (MAT) in control, 2 and 16 h ABT pretreatment groups were 0.3, 4.6 and 2.9 h, respectively, suggesting delayed absorption. This hypothesis was further supported by GastroPlusTM simulation. In summary, extent of triazolam absorption was increased to a similar extent with both 2 and 16 h ABT pretreatment regimens, suggesting that either of the regimen can be used to increase parent exposures in rat. With ABT pretreatment, delayed absorption of triazolam and acetaminophen was observed, as suggested by delay in Tmax and MAT, respectively.

Easy-to-use naloxone formulations are needed to help address the opioid overdose epidemic. The pharmacokinetics of i.v., i.m., and a new i.n. naloxone formulation (2 mg) were compared in six healthy volunteers. Relative to i.m. naloxone, geometric mean (90% confidence interval [CI]) absolute bioavailability of i.n. naloxone was modestly lower (55%; 90% CI, 43-70% vs. 41%; 90% CI, 27-62%), whereas average (±SE) mean absorption time was substantially shorter (74 ± 8.8 vs. 6.7 ± 4.9 min). The opioid-attenuating effects of i.n. naloxone were compared with i.m. naloxone (2 mg) after administration of oral alfentanil (4 mg) to a separate group of six healthy volunteers pretreated with 240 mL of water or grapefruit juice. The i.m. and i.n. naloxone attenuated miosis by similar extents after water (40 ± 15 vs. 41 ± 21 h*%) and grapefruit juice (49 ± 18 vs. 50 ± 22 h*%) pretreatment. Results merit further testing of this new naloxone formulation.

The oral pharmacokinetics of diclofenac (DF) were evaluated in cattle by analyzing plasma concentration-time data after its intravenous and oral administration in order to propose the oral administration of DF as effective route to avoid long withdraw period. DF was intravenously and orally administered at 1 mg/kg to cattle using a crossover design with a 4-week washout period. Plasma concentrations of DF were determined by a HPLC analysis. The mean absorption time (MAT) and absorption half-life (t1/2ka) were 1.61 ± 0.61 and 1.51 ± 0.38 hr, respectively, and bioavailability was nearly 100%. The oral pharmacokinetics of acetaminophen (AAP) were also evaluated in cattle. Plasma concentrations of AAP were determined by a HPLC analysis. MAT and t1/2ka were 2.85 ± 0.93 and 1.53 ± 0.28 hr, respectively, and bioavailability was approximately 70%. In conclusion, the results of the present study indicate that DF and AAP are rapidly absorbed from the forestomach of cattle. Therefore, the appropriate efficacies of these drugs may be achieved via their oral administration, even in cattle.

We study the one-dimensional motion of a Brownian particle inside a confinement described by two reactive boundaries which can partially reflect or absorb the particle. Understanding the effects of such boundaries is important in physics, chemistry and biology. We compute the probability density of the particle displacement exactly, from which we derive expressions for the survival probability and the mean absorption time as a function of the reactive coefficients. Furthermore, using the Feynman-Kac formalism, we investigate the reaction time profile, which is the fluctuating time spent by the particle at a given location, both till a fixed observation time and till the absorption time. Our analytical results are compared to numerical simulations showing perfect agreement., 30 pages, 7 figures

The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2) = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure.

Intestinal P-glycoprotein is regio-selectively expressed and is a high affinity, low capacity efflux carrier for the cationic, poorly permeable trospium. Organic cation transporter 1 (OCT1) provides lower affinity but higher capacity for trospium uptake. To evaluate regional intestinal permeability, absorption profiles after gastric infusion of trospium chloride (30 mg/250 ml = [I]2) for 6 h and after swallowing 30 mg immediate-release tablets in fasted and fed healthy subjects, were evaluated using an inverse Gaussian density function to model input rate and mean absorption time (MAT). Trospium chloride was slowly absorbed (MAT ∼10 h) after gastric infusion involving two processes with different input rates, peaking at about 3 h and 7 h. Input rates and MAT were influenced by dosage form and meal. In conclusion, trospium is absorbed from two “windows” located in the jejunum and cecum/ascending colon, whose uptake capacity might result from local abundance and functional interplay of P-glycoprotein and OCT1.

Because of its slow systemic absorption and flip-flop kinetics, ropivacaine's pharmacokinetics after a peripheral nerve block has never been thoroughly characterized. The purpose of this study was to develop a population pharmacokinetic model for ropivacaine after loco-regional administration and to identify patient characteristics that may influence the drug's absorption and disposition. Frequent plasma samples were taken up to 93 h after a 100 mg dose given as femoral block for postoperative analgesia in 15 orthopedic patients. Ropivacaine plasma concentration-time data were analyzed using a nonlinear mixed effects modeling method. A one-compartment model with parallel inverse Gaussian and time-dependent inputs best described ropivacaine plasma concentration-time curves. Ropivacaine systemic absorption was characterized by a rapid phase (mean absorption time of 25 ± 4.8 min) followed by a much slower phase (half-life of 3.9 ± 0.65 h). Interindividual variability (IIV) for these parameters, 58 and 9 %, indicated that the initial absorption phase was more variable. The apparent volume of distribution (V/F = 77.2 ± 11.5 L, IIV = 26 %) was influenced by body weight (Δ 1.49 % per kg change) whereas the absorption rate constant (slower phase) of ropivacaine was affected by age (Δ 2.25 % per year change). No covariate effects were identified for the apparent clearance of the drug (CL/F =10.8 ± 1.0 L/h, 34 IIV = 34 %). These findings support our hypothesis that modeling a complex systemic absorption directly from plasma concentration-time curves exhibiting flip-flop kinetics is possible. Only the age-effect was considered as relevant for possible dosing adjustments.

The aim of this study was to verify the values of maximal observed concentration (C max,obs) and the time, at which maximum concentration is observed (t max,obs) using the analysis of the absorption rate constant (k ab). It focused on the changes in concentration over time (C-T) for drugs, for which several peaks of concentration occur. In addition, the attempt was made to use Fibonacci sequence to facilitate the visual analysis of the dynamics in changes of concentration on C-T graphs. The analyses were conducted with the use of three hypothetical data groups (groups I, II and III), which had distinct C-T profiles, and with the in vivo data form healthy subjects (n = 10) taking part in a bioequivalence study, who was given a single oral dose of topiramate (100 mg). The comparison of hypothetical and real in vivo data demonstrated that for the C-T curves, in which there are several peaks of concentration C max,obs and t max,obs values can easily be miscalculated when the increase in concentration is not properly related to the appropriate absorption phase (63.2, 87.50, 96.88 %). It was also demonstrated that the data transformation with the use of Fibonacci sequence exposes slight differences in the observed concentration values in a semi-logarithmic scale. The results of this study show that in case of C-T curves with several peaks of concentration, the verification of C max and t max data obtained taking into account different absorption phases enables more precise evaluation of these parameters.

The present study reports the significance of polymeric nanoparticles in oral drug delivery from pharmacokinetic perspective. Impact of different dose polymeric nanoparticulate formulations on various pharmacokinetic parameters has been reported. All nano-formulations were found to have significant effect on important pharmacokinetic parameters like Cmax, Tmax, AUC, absolute bioavailability, absorption rate constant (Ka), elimination rate constant (Kel), elimination half life (t1/2), mean residence time (MRT) and mean absorption time (MAT). Further, drug in polymeric nanoparticles exhibited the flip-flop pharmacokinetics suggesting its slow and sustained release from the polymeric matrix. Together, polymeric nanoparticles hold promise for the oral delivery of molecules having pharmacokinetic hurdles in their delivery approach. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3730–3734, 2009

The pharmacokinetics of doxycycline were investigated in sheep after oral (PO) and intravenous (IV) administration. The IV data were best described using a 2- (n = 5) or 3- (n = 6) compartmental open model. Mean pharmacokinetic parameters obtained using a 2-compartmental model included a volume of distribution at steady-state (V(ss)) of 1.759+/-0.3149L/kg, a total clearance (Cl) of 3.045+/-0.5264mL/kg/min and an elimination half-life (t(1/2beta)) of 7.027+/-1.128h. Comparative values obtained from the 3-compartmental mean values were: V(ss) of 1.801+/-0.3429L/kg, a Cl of 2.634+/-0.6376mL/kg/min and a t(1/2beta) of 12.11+/-2.060h. Mean residence time (MRT(0-infinity)) was 11.18+/-3.152h. After PO administration, the data were best described by a 2-compartment open model. The pharmacokinetic parameter mean values were: maximum plasma concentration (C(max)), 2.130+/-0.950microg/mL; time to reach C(max) (t(max)), 3.595+/-3.348h, and absorption half-life (t(1)/(2k)(01)), 36.28+/-14.57h. Non-compartmental parameter values were: C(max), 2.182+/-0.9117microg/mL; t(max), 3.432+/-3.307h; F, 35.77+/-10.20%, and mean absorption time (MAT(0-infinity)), 25.55+/-15.27h. These results suggest that PO administration of doxycycline could be useful as an antimicrobial drug in sheep.

The purpose of this study was to investigate the pharmacokinetics of ceftriaxone after single intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) doses in healthy dogs. Six mongrel dogs received ceftriaxone (50 mg/kg) by each route in a three-way crossover design. Blood samples were collected in predetermined times after drug administration. Results are reported as mean +/- standard deviation (SD). Total body clearance (Cl(t)) and apparent volume of distribution (V(z)) for the i.v. route were 3.61 +/- 0.78 and 0.217 +/- 0.03 mL/kg, respectively. Terminal half-life harmonic mean (t(1/2 lambda)) was 0.88; 1.17 and 01.73 h for the i.v., i.m and s.c. routes, respectively. Mean peak serum concentration (C(max)) was 115.10 +/- 16.96 and 69.28 +/- 14.55 microg/mL for the i.m and s.c. routes, respectively. Time to reach C(max) (t(max)) was 0.54 +/- 0.24 and 1.29 +/- 00.64 h for the i.m and s.c. routes, respectively. Mean absorption time (MAT) was 1.02 +/- 0.64 and 2.23 +/- 00.73 h for the i.m and s.c. routes, respectively. Bioavailability was 102 +/- 27 and 106 +/- 14% for the i.m and s.c. routes, respectively. Statistically significant differences were determined in C(max), t(max), MAT and t(1/2 lambda) of s.c. administered ceftriaxone when compared with the i.v and i.m. routes. These findings suggest that once or twice s.c. or i.m. daily administered ceftriaxone should be adequate to treat most susceptible infections in dogs.

We consider diffusion in arbitrary spatial dimension d with the addition of a resetting process wherein the diffusive particle stochastically resets to a fixed position at a constant rate $r$. We compute the non-equilibrium stationary state which exhibits non-Gaussian behaviour. We then consider the presence of an absorbing target centred at the origin and compute the survival probability and mean time to absorption of the diffusive particle by the target. The mean absorption time is finite and has a minimum value at an optimal resetting rate $r^*$ which depends on dimension. Finally we consider the problem of a finite density of diffusive particles, each resetting to its own initial position. While the typical survival probability of the target at the origin decays exponentially with time regardless of spatial dimension, the average survival probability decays asymptotically as $\exp -A (\log t)^d$ where $A$ is a constant. We explain these findings using an interpretation as a renewal process and arguments invoking extreme value statistics., 21 pages, 3 figures, submitted to Journal of Physics A

Ventilator-associated pneumonia (VAP) caused by methicillin-resistant Staphylococcus aureus is a major cause of mortality in mechanically ventilated patients. Nebulization of teicoplanin is an alternative way of administration that may provide higher lung tissue concentrations than intravenous (IV) delivery. The aim of this study was to compare the administration of teicoplanin via aerosol with the IV route by measuring the lung and the serum teicoplanin concentrations in a rat model.Eighty healthy male Sprague-Dawley rats were anesthetized and received a single dose of teicoplanin by the IV or aerosol route. After sacrifice, lung and blood samples were collected and teicoplanin concentrations were measured with fluorescence polarization. A noncompartmental approach was used. The area under the concentration curve/minimal inhibition concentration ratio (AUC/MIC), AUC, absorbed fraction, mean residence time (MRT), and mean absorption time (MAT) of teicoplanin were calculated.Mean±SD lung tissue concentrations of teicoplanin in the aerosol group were significantly higher than those in the IV group (p0.0001). The mean lung tissue concentration achieved at 15 min was 1.94±1.33 mg/g in the aerosol group and 0.04±0.01 mg/g in the IV group. The mean AUClung was 67.4 mg hr(-1)g(-1) after aerosol and 0.8 mg hr(-1)g(-1) after the IV route. In the aerosol group, AUCserum/MIC ratio was 605/2, and in the IV route, AUCserum/MIC ratio was 682/2. MAT was longer after aerosol than after the IV route (0.91 hr versus 0.06 hr), and MRT was longer after aerosol than after IV bolus administration (6.52 hr versus 5.61 hr).Teicoplanin concentrations in the lung tissue of the rat model were significantly higher by the aerosol route than by the IV route. The AUClung after nebulization was 84 times higher than delivery by the IV route, and the AUClung/MIC ratio after nebulization met the recommended target to eradicate Staphylococcus aureus. Administration of teicoplanin by the aerosol route could represent one of the new therapeutic weapons of the treatment of the VAP.

Purpose. The sensitivity and effectiveness of indirect metrics proposedfor the assessment of comparative absorption rates in bioequivalencestudies [Cmax, Tmax, partial AUC(AUCp), feathered slope (SLf), interceptmetric (I)] were originally tested by assuming first-order absorption.The present study re-evaluates their sensitivity performances using themore realistic inverse Gaussian (IG) model characterizing the inputprocess for oral drug administration.

The effects of anaesthesia on intestinal drug absorption and hepatic first-pass metabolism in rats were investigated by observing the difference in the drug concentration between portal and systemic bloods. Oxacillin and pentobarbital were selected as a model drug and as an anaesthetic, respectively. Rats were divided into a conscious control group and an anaesthetized group. All rats were cannulated simultaneously in the portal vein and in the femoral artery, and oxacillin was orally administered after its intra-arterial injection (double dosing). For the anaesthetized group, pentobarbital was intrasubcutaneously administered twice, first before intra-arterial injection and again before oral administration of oxacillin. The arterial blood alone was sampled from the cannula in the femoral artery before oral administration, whereas the arterial and portal bloods were simultaneously sampled from both cannulated sites after oral administration. Oxacillin concentrations in plasma were assayed by HPLC. The anaesthesia increased the absolute bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (FH), but caused little change in the local absorption ratio into the portal system (Fa) and the total clearance (CL). The hepatic clearance (CLH) was significantly decreased, resulting in an apparent small change in CL—CLH which is considered to be renal clearance. By this method, it was shown directly that an increase in F due to pentobarbital anaesthesia was attributable to the significant increase in FH. It is expected that the method is useful not only to evaluate the effect of anaesthesia on the first-pass effect, but also to assess the effect of co-administration of drugs on first-pass metabolism.

Liposomal formulation containing cyclosporine A (CSA) were prepared. The most stable liposomes with the composition of CSA, dipalmitoylphosphatidyl choline (DPPC) and cholesterol (Chol.) in molar ratio 1:0.2:1, respectively were administered orally to New Zealand rabbits. The pharmacokinetic of the administered CSA was compared with that of the commercially available oily oral formulation of CSA (Sandimmune) at dose of 15 mg/kg. Cyclosporine concentration in blood was monitored using a radioimmunoassay method (RIA). A change in the pharmacokinetic parameters of CSA due to liposomal encapsulation was observed. A peak concentration was reached in 50 min in case of liposomes compared with 225 min in case of Sandimmune. The rate of absorption ( C max /AUC 0–∞ ) was significantly faster following the liposome administration. A significant difference in the area under the concentration curve (AUC 0–∞ ) was found and this was attributed to the difference in the terminal half-lives ( t 1/2 β ) which were 8.88±1.94 and 19.3±8.48 h for liposomes and Sandimmune preparations, respectively. The mean residence time (MRT) and the mean absorption time (MAT) were dramatically decreased following the administration of liposomal formulation. Generally, there was less inter-individual variation in the values of rate of absorption, t 1/2 β and MRT when CSA liposomes were orally administered compared to the administration of Sandimmune. Thus, an oral liposomal formulation for CSA can be developed to offer the advantages of low variability and fast onset of action.

The in-vivo absorption characteristics of 5-fluorouracil (5-FU) encapsulated within ethylcellulose microspheres, prepared by an evaporation/extraction method, were evaluated in rabbits. 5-FU was administered as a solution both intravenously ( n =5, 12 mg/kg) and orally as a single dose ( n =6, 20 mg/kg), and orally as microspheres ( n =5, 20 mg/kg). Statistically significant differences were found between the two oral treatments. The mean residence time and mean absorption time were both considerably increased following microsphere administration compared with the solution. The absolute bioavailabilities of 5-FU from the solution and the microspheres were 5 and 17%, respectively.

The plasma pharmacokinetics of danofloxacin administered at 1.25 mg kg-1 body weight by the intravenous and intramuscular routes were determined in sheep. Tissue distribution was also determined following administration by the intramuscular route at 1.25 mg kg-1 body weight. Danofloxacin had a large volume of distribution at steady state (Vdss) of 2.76 +/- 0.16 h (mean +/- S.E.M.) L kg-1, an elimination half-life (t1/2 beta) of 3.35 +/- 0.23 h, and a body clearance (C1) of 0.63 +/- 0.04 L kg-1 h-1. Following intramuscular administration it achieved a maximum concentration (Cmax) of 0.32 +/- 0.02 microgram mL-1 at 1.23 +/- 0.34 h (tmax) and had a mean residence time (MRT) of 5.45 +/- 0.19 h. Danofloxacin had an absolute bioavailability (F) of 95.71 +/- 4.41% and a mean absorption time (MAT) of 0.81 +/- 0.20 h following intramuscular administration. Mean plasma concentrations of > 0.06 microgram mL-1 were maintained for more than 8 h following intravenous and intramuscular administration. Following intramuscular administration highest concentrations were measured in plasma (0.43 +/- 0.04 microgram mL-1), lung (1.51 +/- 0.18 micrograms g-1), and interdigital skin (0.64 +/- 0.18 microgram g-1) at 1 h, duodenal contents (0.81 +/- 0.40 microgram mL-1), lymph nodes (4.61 +/- 0.35 micrograms g-1), and brain (0.06 +/- 0.00 microgram mL-1) at 2 h, jejunal (10.50 +/- 4.31 micrograms mL-1) and ileal (5.25 +/- 1.67 micrograms mL-1) contents at 4 h, and colonic contents (8.94 +/- 0.65 micrograms mL-1) at 8 h.

A new method has been developed for simultaneous evaluation of local absorption from the intestine into the portal system and local disposition through the liver, and for assessment of the bioavailability of a drug in a single conscious rat. The method is based on the difference between plasma concentrations in portal and systemic blood (PS method). Because cephalexin is known to be absorbed completely from the intestine and not to be eliminated through the liver, it was used as test drug to confirm the validity of the new method. The portal vein and the femoral artery of a rat were simultaneously cannulated and blood samples were obtained from both sites. Two methods of administration, single-dosing and double-dosing, were investigated and the efficacy of double-dosing (DD) was demonstrated. Rats received an intra-arterial (group A) or oral (group B) dose in single-dosing, whereas rats used for double-dosing received an oral dose 3 h after an intra-arterial dose (group C). After administration of cephalexin, the portal and arterial plasma concentrations were determined by HPLC. Groups A and B were monitored for 4 h and group C for 8 h. The portal-blood flow rate was measured by means of an electromagnetic flow-meter. Global and local moments were calculated by trapezoidal integration with extrapolation to infinite time. On the basis of the PS method, the local absorption ratio (Fa) and the mean local absorption time (t̄a) were estimated to be 0.975 ± 0.104 and 2.19 ± 0.51 h, respectively, in group B. By comparing the averaged moments between groups A and B, the extent of bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (FH) were calculated to be 1.01, 1.92 h and 1.04, respectively. The mean hepatic transit time (t̄H) was negligible. In group C, Fa = 0.936 ± 0.107, t̄H = 1.55 ± 0.32 h, F = 1.08 ± 0.07, MAT = 1.55 ± 0.40 h and FH = 1.17 ± 0.14 h, the mean values being close to those from groups A and B. In conclusion, the PS method with short-period double-dosing (PS-DD method) can offer an effective means of evaluating the local absorption kinetics of drugs, because F, MAT and FH are obtained from a single conscious rat, and consequently the standard deviations of the quantities can be quickly estimated.

Plasma pharmacokinetics of ranitidine HCl were investigated after intravenous (i.v.) and oral (p.o.) administration of drug to six healthy foals. Twelve- to sixteen-week-old foals received 2.2 mg ranitidine/kg i.v. and 4.4 mg ranitidine/kg p.o. Concentrations of ranitidine were determined using normal phase high performance liquid chromatography. Plasma concentrations of ranitidine HCl declined from a mean of 3266 ng/mL at 5 min to 11 ng/mL at 720 min after administration. The profile of the plot of concentrations of ranitidine HCl vs. time was best described by a two-exponent equation for two foals; data for the remaining four foals were best described by a three-exponent equation. Mean values for model-independent values were: apparent volume of distribution (Vdss) = 1.46 L/kg; area under the curve (AUC) = 167,442 ng.min/mL; area under the moment curve (AUMC) = 18,068,221 ng.min2/mL; mean residence time (MRT) = 108.9 min; and clearance (Cl) = 13.3 mL/min.kg. Following p.o. administration, a two-exponent equation best described data for five foals; data for the remaining foal were best described by a three-exponent equation. Mean values of the pharmacokinetic values from the p.o. study include: AUC = 126,413 ng.min/mL; AUMC = 18,039,825 ng.min2/mL; mean absorption time (MAT) = 32.0 min; observed time to maximum plasma concentration (Tmax) = 57.2 min; maximum observed plasma concentration (Cmax) = 635.7 ng/mL; and bioavailability (F) = 38%.

To evaluate the effect of foal age on the pharmacokinetics of cefadroxil, five foals were administered cefadroxil in a single intravenous dose (5 mg/kg) and a single oral dose (10 or 20 mg/kg) at ages of 0.5, 1, 2, 3 and 5 months. Pharmacokinetic parameters of terminal elimination rate constant (beta(po)), oral mean residence time (MRTpo), mean absorption time (MAT), rate constant for oral absorption (Ka), bioavailability F, peak serum concentrations (Cmax) and time of peak concentration (tmax), were evaluated in a repeated measures analysis over dose. Across animal ages, parameters for the intravenous dose did not change significantly over animal age (P > or = 0.05). Mean values +/- SEM were: beta(IV) = 0.633 +/- 0.038 h-1; Cl = 0.316 +/- 0.010 L/kg/h; Vc = 0.196 +/- 0.008 L/kg; Varea = 0.526 +/- 0.024 L/kg; VSS = 0.374 +/- 0.014 L/kg; MRTiv = 1.22 +/- 0.07 h; Kel = 1.67 +/- 0.08 h-1. Following oral administration, drug absorption became faster with age (P < 0.05), as reflected by MRTpo, MAT, Ka and tmax. However, oral bioavailability (+/- SE) declined significantly (P < 0.05) from 99.6 +/- 3.69% at 0.5 months to 14.5 +/- 1.40% at 5 months of age. To evaluate a dose effect on the pharmacokinetic parameters, a series of oral doses (5, 10, 20 and 40 mg/kg) were administered to these foals at 1 month of age. beta(po) (0.548 +/- 0.023 h-1) and F (68.26 +/- 2.43%) were not affected significantly by the size of the dose. Cmax was approximately doubled with each two-fold increase in dose: 3.15 +/- 0.15, 5.84 +/- 0.48, 12.17 +/- 0.93 and 19.71 +/- 2.19 micrograms/mL. Dose-dependent kinetics were observed in MRTpo, MAT, Ka and tmax.

Plasma pharmacokinetics of ranitidine HCl were investigated after intravenous (i.v.) and oral (p.o.) administration of 2.2 mg/kg drug to six healthy adult horses. Concentrations of ranitidine were determined using normal-phase, high-performance liquid chromatography. Plasma concentrations of ranitidine HCl declined from a mean of 5175 ng/mL at 5 min to 37 ng/mL at 720 min after i.v. administration. A three-exponent equation, Cp = A1 x e-k1t + A2 x e-k2t + A3 x e-k3t, best described data for all horses. Mean values for model-independent values calculated from the last quantifiable time point were: apparent volume of distribution (Vdss) = 1.07 L/kg; area under the curve (AUC) = 231,000 ng.min/mL: area under the moment curve (AUMC) = 26,900,000 ng.min2/mL; mean residence time (MRT) = 113 min; and clearance (Cl) = 9.8 mL/min.kg. Following p.o. administration, a two-exponent equation, Cp = A1 x e-k1t + A2 x e-k2t, best described the data for five horses: data for the remaining horse were best described by a three-exponent equation. Mean values of pharmacokinetic values from the p.o. study include: AUC = 59,900 ng x min/mL; AUMC = 10,600,000 ng x min2/mL; mean absorption time (MAT) = 58.9 min: Tmax = 99.2 min; Cmax = 237 ng/mL: and F = 27%.

A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration.

1. The pharmacokinetics of levofloxacin were investigated in Japanese quails after a single dose of 10 mg/kg BW, given either intravenously or orally. 2. Following intravenous administration, the mean value of distribution at steady state (Vd(ss)), total body clearance (Cl(tot)) and mean residence time (MRT) of levofloxacin were 1·25 l/kg, 0·39 l/h/kg and 2·72 h, respectively. 3. Following oral administration of levofloxacin, the peak plasma concentration (C(max)) was 3·31 µg/ml and was achieved at a maximum time (T(max)) of 2 h. Mean residence time (MRT), mean absorption time (MAT) and bioavailability were 4·26 h, 1·54 h and 69·01%, respectively. In vitro plasma protein binding of levofloxacin was 23·52%. 4. Based on pharmacokinetic and pharmacodynamic integration, an oral dose of 10 mg/kg levofloxacin for every 12 h is recommended for a successful clinical effect in quails.

This investigation was carried out to evaluate the absorption characteristics of experimental meclofenamate sustained-release microcapsules, prepared by an emulsion-solvent evaporation method using high molecular weight cellulose propionate polymer and polyethylene glycol (PEG) 2000 in a ratio of 1:2:1 drug:polymer:PEG, using eight male beagle dogs. Meclofenamate was administered intravenously at a dose of 40 mg and orally as a single dose (50 mg) of conventional capsules (Meclomen®), oral solution and microcapsules on four separate occasions. Statistically significant differences were observed between the microcapsules and the other two oral treatments in both the peak plasma concentration ( C max ) and the time of peak concentration ( T max ). No significant difference was found between the three oral treatments in the area under the plasma concentration-time curve (AUC), indicating a comparable extent of absorption. The absorption rate ( C max /AUC) was significantly slower following the administration of microcapsules. Both the mean residence time (MRT) and the mean absorption time (MAT) were dramatically increased following oral administration of the microcapsules compared to the conventional capsules and the oral solution. The mean (in-vivo) dissolution time (MDT) for the prepared microcapsules was 2.14 h and for the conventional capsules 0.3 h, which were found to be consistent with the in-vitro availability of the drug. Duncan's multiple range test indicated no significant difference between the oral solution and the conventional capsules in any of the calculated pharmacokinetic parameters. The absolute bioavailability from the oral solution, the conventional capsules and the experimental microcapsules was 74.6, 67.9 and 72.5%, respectively.

Purpose. Flexible parametric models describing the input process after extravascular drug administration are needed for the assessment of absorption rate and the use of population methods in bioavailability and bioequivalence studies. Methods. The oral concentration-time curve modeled as the product of the input and disposition function in the Laplace domain was obtained by numerical inversion methods for parameter estimation. The utility of the inverse Gaussian input density was examined using bioavailability data of an extended-release dosage form. Measures of rate of absorption and the cumulative absorbed amount profile were defined in terms of the estimated model parameters. Results. Accurate estimation of absorption parameters was achieved by simultaneous fitting of the extravascular and intravascular data (describing the latter by a triexponential function). The new input function allowed a direct estimation of both extent of absorption and mean absorption time. Conclusions. The findings suggest that the inverse Gaussian density is a useful input function. Its flexibility may reduce the effect of model misspecification in parameter estimation. All parameters can be readily interpreted in terms of the absorption process.

The in vivo absorption characteristics of metoclopramide hydrochloride microspheres prepared from cellulose propionate polymer by an emulsion-solvent evaporation method were evaluated using six male beagle dogs. Metoclopramide was administered intravenously at a dose of 4 mg and orally as a single dose (10 mg) of microspheres and conventional tablets (Plasil®) on three separate occasions. Statistically significant differences were found between the two oral treatments in both the time and magnitude of the peak generated (p < 0.05). The absorption rate (Cmax/AUC) was significantly slower following the administration of microspheres. No significant difference was found between the two treatments in the area under the plasma concentration-time curve (AUC), indicating a comparable extent of absorption. The mean residence time (MRT) and mean absorption time (MAT) were dramatically increased following microsphere administration compared to the conventional tablets. The absolute bioavailability of metoclopramide from the microspheres and the conventional tablets was 72 and 65%, respectively. The in vivo results were found to be consistent with the in vitro availability of the drug.

Purpose. The purpose of this paper is to report the study on the first-pass accumulation kinetics of salicylic acid (SA) in gut tissue after absorption by simultaneously analyzing drug contents in the lumen, gut tissue, and blood in anesthetized rats. Methods. Sodium salicylate (5.4 mg as SA) in 0.4 ml normal saline was administered into a closed 10-cm jejunal loop. Drained mesenteric blood from the loop area was collected every minute, while lost blood was replaced through infusion of oxygenated blood from donor rats. At 3, 10, 20, 40, or 60 min after dosing, SA remaining in lumen, accumulating in gut tissue, and appearing in blood were analyzed by HPLC. All the data were fitted into a linear two-consecutive (lumen and gut tissue) first-order kinetic model. Results. After absorption, significant amounts of SA accumulated in gut tissue before appearing in blood, e.g., at 3 or 20 min after dosing, 74.4 or 54.4% of absorbed SA accumulated in gut tissue, respectively. Practically all administered SA was recovered. The estimated mean absorption time from the lumen and mean transit time in gut tissue of SA were 20.4 and 18.5 min, respectively. Conclusions. The above results indicate that gut tissue may act as a reservoir for drug accumulation during the first pass after oral absorption. Thus, the rate of transport of drug into blood circulation after oral administration may significantly differ from the true rate of absorption through the gut membrane. The potential transport resistance from gut tissue to blood should probably be considered in the modeling of GI absorption.

Pharmacokinetics of large molecules, such as rG-CSF and erythropoietin after subcutaneous administration, was discussed based mainly upon the observations of kinetics of rG-CSF and other molecules. The mean absorption time (MAT) and the variance of absorption time (VAT) of rG-CSF were calculated, and the ratio of VAT/(MAT)2 was less than 1, suggesting that the absorption process might be catenary process. The absorption processes of large molecules might consist of molecule independent and dependent processes. The kinetics of erythropoietin suggested that the injection volume might contribute to the molecule independent process.

Introduction Single-dose pharmacokinetics of orbifloxacin (2.5 mg/kg body weight) were determined in clinically normal female Patanwadi sheep (n = 6) following intravenous and intramuscular administration. Methods Orbifloxacin concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration–time data were analyzed by non-compartmental kinetic method. Results and discussion Following a single intravenous injection, an elimination half-life (t1/2β) of 8.31 ± 0.102 h. Steady-state volume of distribution (Vdss) and total body clearance (ClB) were 3.09 ± 0.282 L/kg and 0.158 ± 0.006 L/kg/h, respectively. Following intramuscular administration, an elimination rate constant (β), the area under the curve from zero to infinity (AUC0 − ∞) and the mean absorption time (MAT) were 0.015 ± 0.001 h− 1, 23.49 ± 1.722 μg·h/mL and 7.50 ± 0.58 h, respectively. The peak plasma concentration (Cmax) of 1.81 ± 0.005 µg/mL was achieved at 1.00 ± 0.00 h. The mean residence time (MRT) was 26.25 ± 1.083 h and the absolute bioavailability was 150.8 ± 12.35%, respectively. Orbifloxacin could be useful for the treatment of bacterial infections in sheep that are sensitive to this drug.

The effect of food on the bioavailability of bioadhesive containing indomethacin tablets was evaluated on five male beagle dogs. Indomethacin was administered intravenously at a dose of 15 mg and orally in the fasting state and after food intake as a bioadhesive tablet at a dose of 25 mg. After dosing, serial blood samples were collected for a period of 6 h. Indomethacin plasma concentration was determined by a sensitive high-performance liquid Chromatographie assay. Food consumption dramatically reduced the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) by 86 and 76%, respectively. No significant differences were observed in the time to peak concentration (Tmax), mean residence time of the drug in the body (MRT), mean absorption time (MAT), elimination rate constant (Kel) and elimination half-life ( t 1 2 ) between the fasting and postprandial states. The mean gastrointestinal time (MGT) was found to be 0.81 h. The absolute bioavailability of the indomethacin bioadhesive tablets in the fasting state and after meal was 85.4 and 11.8%, respectively. Complexation of the bioadhesive material with the food contents is the most plausible explanation for the decrease in the extent of absorption of indomethacin.

The pharmacokinetics of Cetrorelix acetate (SB-75), [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]LH-RH, a highly potent LH-RH antagonist following i.v. injection and intratracheal instillation (i.t.), were determined in five unanesthetized, awakw sheep in a cross-over design. After i.t. administration the mean terminal t 1 2 was 11.6±5.2 h, similar to the i.v. elimination t 1 2 of 10.1±0.9 h. Mean residence time (MRT) was prolonged to 11.0±3.4 h vs. 5.9±1.3h i.v., and mean absorption time (MAT) was 5.6 ± 3.9 h. Cmax of 134±79 ng/ml was reached after 1.8±0.5 h (tmax). The mean i.t. bioavailability was 15.4±10.6%.

Background The effects of epidurally administered alfentanil may be due in part to its uptake into the systemic circulation. Therefore we examined the systemic absorption kinetics after epidural injection of alfentanil. Methods Pharmacokinetics were determined using a stable isotope method in ten patients, undergoing lower abdominal surgery under general anesthesia. After epidural injection of 0.68 mg deuterium-labeled alfentanil (alfentanil-d5), 1 mg unlabeled alfentanil was administered over 1 h by an intravenous infusion. Blood samples were collected for 12 h. Concentrations of alfentanil and alfentanil-d5 were measured by a combination of gas chromatography and mass fragmentography. The systemic absorption profiles of alfentanil-d5 were determined by deconvolution of the plasma alfentanil-d5 concentrations with the biexponential unit disposition functions, derived from the intravenous data. In addition, data were analyzed by moment analysis. Results The mean (+/- SD) steady-state volume of distribution, total plasma clearance, elimination half-life and mean residence time, derived from the unlabeled alfentanil concentration-time data, were 43.2 +/- 19.5 1,418 +/- 129 ml/min, 119 +/- 34 min, and 103 +/- 26 min, respectively. The absorption of alfentanil-d5 was monophasic in most patients. The mean systemic availability and mean absorption time derived from the deconvolution data were 100 +/- 17% and 114 +/- 24 min. The values determined by moment analysis were 107 +/- 18% and 112 +/- 36 min, respectively. Conclusions After epidural administration alfentanil is slowly absorbed into the general circulation. Resulting plasma concentrations are very low and do not contribute appreciably to the systemic opioid effect.

The unanesthetized awake sheep was employed as large animal model for the determination of bioavailability and pharmacokinetics following the pulmonary instillation of the decapeptide detirelix. After intratracheal administration of a 80 micrograms/kg dose, the average t1/2 of elimination was 9.8 +/- 1.3 hours (n = 5) which was similar to the elimination kinetics of a 30 micrograms/kg i.v. dose (7.2 +/- 2.9 hours). Mean residence time (MRT) was prolonged to 10.3 +/- 2.0 hours vs. 2.7 +/- 0.8 hours i.v., and mean absorption time (MAT) was calculated to be 7.5 +/- 1.8 hours. Maximum plasma levels (cmax) of 9.2 ng/ml were reached after 2 hours. The average bioavailability was 9.8 +/- 3.9% of the dose. The pharmacokinetic profile was found to be similar after aerosol administration. It was concluded that detirelix was absorbed systemically when administered by pulmonary instillation or aerosolization and that the unanesthetized awake sheep is a suitable model to study resulting drug profiles.

Equations for the mean residence times in the body (MRT) and AUMC/AUC of a drug and its metabolite have been derived for an oral drug undergoing first-pass and linear reversible metabolism. The mean residence times of the drug or interconversion metabolite in the body after oral drug are described by equations which include the mean absorption time (MAT), the mean residence times of the drug or metabolite in the body after intravenous administration of the drug, the fractions of the dose entering the systemic circulation as the parent drug and metabolite, and the systemically available fractions of the drug (F p p) or metabolite (F m p). Similarly, the AUMC/AUC of the drug and metabolite after oral drug can be related to the MAT, ratios of the fraction of the dose entering the systemic circulation to the systemically available fraction, the first-time fractional conversion of each compound, and AUMC/AUC ratios after separate intravenous administration of each compound. The F p p and F m p values, in turn, are related to the first-pass availabilities of both drug and metabolite and the first-time fractional conversion fractions. The application of these equations to a dual reversible two-compartment model is illustrated by computer simulations.

The aim of the present study was to evaluate the bioavailability of a drug from rapidly disintegrating tablets prepared using fine spherical crystalline cellulose (PH-M-06) and spherical sugar granules (Nonpareil, NP). Rapidly disintegrating tablets containing acetaminophen as the model drug in combination with a mixture of NP-108 (purified n-mannitol) and PH-M-06 were prepared. Plasma concentration profiles and pharmacokinetic parameters of acetaminophen in rabbits were investigated after oral administration of the prepared tablets. No significant difference in Cmax and AUC(0-infinity) of acetaminophen between rapidly disintegrating tablets and conventional tablets was observed after direct administration of these tablets into the stomach of rabbits. However, tmax (15 min) of acetaminophen from rapidly disintegrating tablets was significantly (p

To determine the pharmacokinetics and bioavailability of florfenicol in the plasma of healthy Japanese quail (Coturnix japonica).Sixty-five quail were given an I/V and I/M dose of florfenicol at 30 mg/kg bodyweight (BW). A two-period sequential design was used, with a wash-out period of 2 weeks between the different routes of administration. Concentrations of florfenicol in plasma were determined using high-performance liquid chromatography (HPLC).A naïve pooled data analysis approach for the plasma concentration-time profile of florfenicol was found to fit a non-compartmental open model. After I/V administration, the mean residence time (MRT), mean volume of distribution at steady state (Vss), and total body clearance of florfenicol were 12.0 (SD 0.37) h, 8.7 (SD 0.22) L/kg, and 1.3 (SD 0.08) L/h/ kg, respectively. After I/M injection, the MRT, mean absorption time (MAT), and bioavailability were 12.3 (SD 0.37) h, 0.2 (SD 0.02) h, and 79.1 (SD 1.79)%, respectively.The time for the concentration of florfenicol to fall below the probable effective concentration of 1 microg/ ml of approximately 10 h is sufficient for the minimum inhibitory concentration needed for many bacterial isolates. Further pharmacodynamic studies in quail are needed to evaluate a suitable dosage regimen.