Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus.

A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CL(CR)) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49.(CL(CR)/57) liter/h (57 was the mean population value of CL(CR)); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h(-1); bioavailability was 0.825; and lag time was 0.382 h. The CL(CR) was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure.

Biological stability and osteoconductivity in rabbit tibia of pulsed laser deposited hydroxylapatite coatings.

A comparative study of the biological stability and the osteoconductivity of hydroxylapatite (HA) coatings produced by pulsed laser deposition (PLD) and plasma spraying (PS) was conducted. Three different implant groups were used: grit-blasted titanium rods coated with HA-PLD (2-microm-thick), grit-blasted titanium rods coated with HA-PS (50-microm-thick), and uncoated. Implantation took place into the proximal tibia of 12 mature New Zealand White rabbits for 24 weeks. Samples were evaluated using descriptive histology and histomorphometry. While HA-PS implants showed considerable instability and reduction in thickness after 24 weeks, but no statistical difference to the titanium group, the HA-PLD group showed a significant higher amount of bone apposition (Scheffé test, p<0.05) than the other two groups, without signs of degradation or dissolution. Remarkably, after 6 months, the almost intact thin pulsed laser deposited coating could be observed by electron microscopy in extended areas.

Estimation of transdermal permeation parameters in non-stationary diffusion experiments. Application to pre-treatment studies with terpenes.

PURPOSE: To estimate the applicability of transdermal drug permeation parameters in a finite-dose model for skin pre-treated with terpenes and to evaluate the enhancing effect of some terpene formulations on alprazolam permeation. METHODS: In vitro enhancement of alprazolam human skin permeation was investigated using a pretreatment with different terpene solutions. Vertical diffusion, Franz-type cells were used. Intrinsic drug permeation was also investigated. Transdermal permeation parameters were estimated from the permeation tabulates using different theoretical approaches for their calculation. Two groups of permeation parameters were calculated: modelistic (diffusion of a finite-dose of drug model) and parameters nondependent of a diffusional model. RESULTS: In control experiments, all approaches of data treatment satisfactorily described the experimental permeation profiles. When skin pre-treatment was investigated, the fitting of a mathematical sigmoid function was much better than the diffusional approach. Pre-treatment of the skin with Limonene dissolved in ethanol / propylene glycol and Menthol dissolved in propylene glycol increased 15 and 10 times respectively the permeation parameters of alprazolam. CONCLUSIONS: Using enhancers that are rapidly cleared from the skin, skin permeability does not remain constant during the permeation experiment and therefore it is not possible to calculate parameters that are usually true coefficients or definite values. In this case, non-modelistic parameters can be used to estimate an enhancing effect.

Pharmacokinetics of a new Autogel formulation of the somatostatin analogue lanreotide after a single subcutaneous dose in healthy volunteers.

The pharmacokinetics/tolerability of lanreotide Autogel have been evaluated. Healthy volunteers (n = 24) first received immediate-release lanreotide as a single subcutaneous (s.c.) injection. After two days, 40 or 60 mg lanreotide Autogel was injected subcutaneously. Blood was sampled at various intervals for 56 days. Systemic/local adverse events and changes in biological profile/vital signs were recorded. Lanreotide Autogel produced a prolonged-release pharmacokinetic profile: mean area under the serum concentration-time curve from time 0 to infinity (AUC) was 53.73 +/- 8.99 and 79.48 +/- 13.06 ng mL(-1) day for 40 and 60 mg, respectively, mean peak serum concentration (C(max)) was 4.38 +/- 2.91 and 5.71 +/- 3.52 ng mL(-1), respectively, median time to reach C (minimum-maximum) was 0.50 (0.083-18.0) and 0.38 (0.083-9.01) days, respectively, mean apparent elimination half-life was 21.63 +/- 9.42 and 22.01 +/- 9.87 days, respectively, and relative bioavailability was 0.93 +/- 0.12 and 0.82 +/- 0.15, respectively. Thus, lanreotide Autogel exhibited linear pharmacokinetics for the doses studied. Pharmacokinetic profiles were similar in both genders, apart from statistically significant differences in C(max) and C(max)/AUC. The Autogel formulation of lanreotide was well tolerated, with systemic adverse events being mild/moderate. Erythema and a painless subcutaneous induration were the most common local adverse events. Lanreotide Autogel provided a prolonged dosing interval and good tolerability for treating acromegaly and carcinoid syndrome.

Determination of N-acetylcysteine in human plasma by liquid chromatography coupled to tandem mass spectrometry.

An analytical method for the determination of total N-acetylcysteine in human plasma has been developed, validated and applied to the analysis of samples from a phase I clinical trial. The analytical method consists of plasma digestion with dithiothreitol in order to reduce all the oxidized forms of N-acetylcysteine, and extraction with ethyl acetate followed by determination of levels by an LC-MS-MS method. The intra- and inter-assay precision and accuracy of this technique were good and the limit of quantitation was 50 ng/ml of plasma. The concentration working range was established between 50 ng/ml and 1000 ng/ml. This method has been used in the analysis of approximately 800 human plasma samples from a clinical study with 24 volunteers; the precision of the quality controls was in the range 8.7 to 13.4% and the accuracy was in the range -5.9 to 8.5%, expressed as the RSD and the relative error, respectively.

Simultaneous determination of paracetamol and chlorpheniramine in human plasma by liquid chromatography-tandem mass spectrometry.

An analytical method for the determination of paracetamol and chlorpheniramine in human plasma has been developed, validated and applied to the analysis of samples from a phase I clinical trial. The analytical method consists in the extraction of paracetamol and chlorpheniramine with diethyl ether, followed by the determination of both drugs by an LC-MS-MS method, using 2-acetamidophenol as internal standard. The intra-assay and inter-assay precision and accuracy of this technique were good and the limit of quantitation was 0.5 microg/ml of plasma for paracetamol and 0.2 ng/ml for chlorpheniramine. The concentration working range was established between 0.5 microg/ml and 25 microg/ml for paracetamol and between 0.2 ng/ml and 50 ng/ml for chlorpheniramine. This method has been used for analyzing more than 1200 human plasma samples from a clinical study with 24 volunteers.

Pharmacokinetics of the somatostatin analog lanreotide in patients with severe chronic renal insufficiency.

OBJECTIVE: To characterize the pharmacokinetic profile of the somatostatin analog lanreotide in patients with severe chronic renal insufficiency. METHODS: Lanreotide was administered by intravenous bolus (7 microg/kg) to 12 patients with severe chronic renal insufficiency and to 12 healthy subjects. Lanreotide serum levels were determined by a radioimmunoassay procedure from time 0 until 24 hours after the administration. The main pharmacokinetic parameters were estimated by a noncompartmental treatment of data. RESULTS: The total serum clearance of lanreotide was found to be significantly lower in patients with severe chronic renal insufficiency than in healthy subjects (mean +/- SEM values of 0.138 +/- 0.017 L/hr/kg versus 0.244 +/- 0.027 L/hr/kg; P < .005). The initial lanreotide concentration, the elimination half-life, the area under the curve from time zero to 24 hours, and the area under the curve from time zero to infinity were significantly greater in patients with severe chronic renal insufficiency than in healthy subjects (307.45 +/- 79.19 ng/mL versus 127.18 +/- 22.65 ng/mL [P < .05]; 2.39 +/- 0.33 hours versus 1.32 +/- 0.20 hours [P < .005]; 62.55 +/- 9.73 ng/mL x hr versus 32.09 +/- 3.23 ng/mL x hr [P < .005]; and 62.95 +/- 9.78 ng/mL x hr versus 32.30 +/- 3.23 ng/mL x hr [P < .005], respectively). The initial volume of distribution, but not the volume of distribution at steady state, was significantly lower in patients with severe chronic renal insufficiency (0.040 +/- 0.008 L/kg versus 0.092 +/- 0.020 L/kg [P < .05] and 0.110 +/- 0.018 L/kg versus 0.172 +/- 0.046 L/kg [difference not statistically significant], respectively). The mean residence time was similar in both groups (0.77 +/- 0.06 hours versus 0.65 +/- 0.14 hours [difference not statistically significant]). CONCLUSIONS: A reduction in the total serum clearance and a decrease in the initial volume of distribution of lanreotide were observed in patients with severe chronic renal insufficiency treated with one intravenous bolus dose of 7 microg/kg lanreotide.

Absolute bioavailability and absorption profile of cyanamide in man.

A pharmacokinetic study of cyanamide, an inhibitor of aldehyde dehydrogenase (EC1.2.1.3) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in healthy male volunteers following intravenous and oral administration. Cyanamide plasma levels were determined by a sensitive HPLC assay, specific for cyanamide. After intravenous administration cyanamide displayed a disposition profile according to a two-compartmental open model. Elimination half-life and total plasma clearance values ranged from 42.2 to 61.3 min and from 0.0123 to 0.0190 L.kg-1.min-1, respectively. After oral administration of 0.3, 1.0, and 1.5 mg/kg x +/- SEM values of Cmax, tmax (median) and AUC were 0.18 +/- 0.03, 0.91 +/- 0.11, and 1.65 +/- 0.27 micrograms.ml-1; 13.5, 13.5, and 12 min; and 8.59 +/- 1.32, 45.39 +/- 1.62, and 77.86 +/- 17.49 micrograms.ml-1.min, respectively. Absorption was not complete and the oral bioavailability, 45.55 +/- 9.22, 70.12 +/- 4.73, and 80.78 +/- 8.19% for the 0.3, 1.0, and 1.5 mg/kg doses, respectively, increased with the dose administered. The models that consider a first-order absorption process alone (whether with a fixed or variable bioavailability value as a function of dose) or with loss of drug due to presystemic metabolism (with zero-order or Michaelis-Menten kinetics) were simultaneously fitted to plasma level data obtained following 1 mg/kg i.v. and 0.3, 1.0, and 1.5 mg/kg oral administrations. The model that best fit the data was that with a first-order absorption process plus a loss by presystemic metabolism with Michaelis-Menten kinetics, suggesting the presence of a saturable first-pass effect.

Influence of d-limonene on the transdermal penetration of felodipine.

Felodipine is a calcium antagonist, one of the dihydropyridines, with potential application in transdermal therapeutic systems (TTS). Earlier studies reported that the high lag time of this drug limited its potential development in a TTS. The present study analyzes the effect of d-limonene at concentrations of 0.5, 1, 5 and 10% on the transdermal penetration of this drug. The study was performed using a diffusion technique in vitro, with the skin of the hairless rat. d-Limonene significantly reduced the lag time (Tl) to 1.4 h at a concentration of 1% (compared with 9.8 h in its absence). Higher concentrations did not produce a significant decrease in the value of this parameter. The presence of d-limonene in the formulae produces an increase in the permeability constant (Kp) and the flux (J). The relation between this increase and the percentage of d-limonene was non-linear. An asymptotic value was obtained at a concentration of 5%, with increases of 993% and 1570% for Kp and J, respectively.

Determination of the anti-platelet-activating factor BN-50727 and metabolites in human urine by high-performance liquid chromatography using solid-phase extraction.

A sensitive and selective HPLC solid-phase extraction procedure was developed for the determination of platelet-activating factor antagonist BN-50727 and its metabolites in human urine. The procedure consisted in a double solid-phase extraction of the urine samples on cyanopropyl and silica cartridges, followed by an automated solid-phase extraction of the drug and metabolites on CBA cartridges and posterior elution on-line to the chromatographic system for its separation. The method allowed quantitation in the concentration range 10-2400 ng/ml urine for both BN-50727 and the main metabolite, the O-demethylated BN-50727 product. The limit of quantitation for both compounds was 10 ng/ml. The inter-assay precision of the method, expressed as relative standard deviation, ranged from 1.9 to 4.5% for BN-50727 and from 2.5 to 9.0% for the metabolite. The accuracy, expressed as relative error, ranged from -2.4 to 4.2% and from 0.2 to 6.2%, respectively. This paper describes the validation of the analytical methodology for the determination of BN-50727 in human urine and also for its metabolites. The method has been used to follow the time course of BN-50727 and its metabolites in human urine after single-dose administration.

Determination of the anti-platelet-activating factor BN-50727 and its metabolites in human plasma by high-performance liquid chromatography-solid-phase extraction.

A sensitive and selective HPLC-solid-phase extraction procedure was developed for the determination of platelet-activating factor antagonist BN-50727 and its metabolites in human plasma. The procedure consisted of an automated solid-phase extraction of the drug and metabolites on disposable propylcarboxylic acid cartridges, followed by on-line chromatographic separation. The method was linear from 3.75 to 2400 ng/ml and the limit of quantitation for BN-50727 in plasma samples was 3.75 ng/ml. The within-run precision of the method, expressed as relative standard deviation, ranged from 2.1 to 8.1%. The accuracy, expressed as relative error, ranged from -3.5 to 4.0%. For the main metabolite, the O-demethylated BN-50727 product, the method was linear from 7.5 to 2400 ng/ml and the limit of quantitation in plasma was 7.5 ng/ml. The within-run precision ranged from 2.1 to 11.0% and the accuracy from -5.3 to 1.1%. This paper describes the validation of the analytical methodology for the determination of BN-50727 in human plasma and also of its metabolites. The method has been used to follow the time course of BN-50727 and its metabolites in human plasma after administration of single and multiple doses.

Pharmacokinetic study of cicletanine in healthy volunteers.

A pharmacokinetic study of cicletanine, a new class of antihypertensive drugs was performed in ten healthy volunteers after administration of 50 mg single oral dose. Cicletanine plasma and urine concentrations were measured using the HPLC technique. The main pharmacokinetic parameters were estimated applying a non-compartmental approach. The half-life ranged between 4.76 to 17.76 h; the mean oral and renal clearance were 7.3 +/- 2.5 l/h and 0.026 +/- 0.012 l/h, respectively. The urinary excretion of the product ranged between 37.5 and 64.6% of the administered dose, the amount of unchanged drug being negligible (0.4 +/- 0.3%). Both metabolic conjugation pathways glucuronidation and sulphation occurred in a similar extent 23.7 +/- 6.7% and 23.0 +/- 7% respectively. The overall pharmacokinetic parameters obtained in this study agree with those previously reported after the administration of higher doses (75-300 mg) and is in favour of a linear pharmacokinetic behaviour of cicletanine over the dose range of 50 mg to 300 mg.

A comparative in vitro study of transdermal absorption of a series of calcium channel antagonists.

The in vitro transdermal absorption of five calcium channel antagonists (nifedipine, nitrendipine, nicardipine, felodipine, and nimodipine) was studied using the skin of hairless rats as a membrane. The aim of this study was to determine the penetration parameters [permeability constant (Kp), lag time (T1, and flux (J)] as measures of the intrinsic transdermal permeabilities of these drugs, in order to predict the potential capacity of these drugs to be formulated in a therapeutical transdermal system (TTS). Reliable prediction of Kp values, using K'w (extrapolated capacity factor in 100% water) and P (n-octanol-water partition coefficient) values as independent variables in the parabolic, bilinear, and hyperbolic functions, were assayed. Nicardipine showed a higher mean transdermal penetration (Kp; 4.9 x 10(-3) cm.h-1) value than the other dihydropyridines. Nifedipine showed the shortest mean T1 value (5.1 h). The permeability rate constants of the calcium channel antagonists assayed can be predicted from their n-octanol-water partition coefficients, using the parabolic function (r = 0.984, p less than 0.01). Nicardipine would be the most suitable candidate for formulation in a TTS design.

Pharmacokinetics and oral bioavailability of carbimide in man.

A pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0.1, 0.3, 0.6, and 1 mg kg-1 and linear pharmacokinetics were observed for this dose range. Elimination half-life and total plasma clearance values ranged from 42 to 52 min and from 14.4 to 20.5 ml kg-1 min-1, respectively. After oral administration of 1 and 1.5 mg kg-1 of carbimide, elimination half-life values were 75 and 61 min, respectively, being higher than the corresponding value obtained after 0.3 mg kg-1 doses, i.e. 39 min. In all cases, rapid absorption was indicated by tmax values ranging from 10.5 to 15.5 min. Absorption was not complete, the oral bioavailability being 53 per cent and 70 per cent for the 0.3 and 1 mg kg-1 carbimide dose, respectively. The data indicate that there is a first-pass effect for carbimide.

Intestinal absorption kinetics of a series of aminopenicillins and azidocillin. A comparative study in the rat.

Intestinal absorption rate constants of amoxicillin, ampicillin, epicillin, cyclacillin and azidocillin, by means of a static in situ intestinal perfusion method has been estimated. Luminal remaining antibiotic concentrations were determined using a standard microbiological technique. In order to establish statistically better absorption kinetics, five dose levels were used, ranging from 10 to 1000 micrograms/ml, and first order, Michaelis-Menten and combined first-order and Michaelis-Menten differential model equations were fitted to experimental data found for each antibiotic. According to the AIC test, the best equation for absorption kinetics was selected. Amoxicillin and ampicillin absorption mechanisms were better described by combined kinetics, while for cyclacillin and epicillin the most probable kinetics was that of Michaelis-Menten. For azidocillin, the only non-aminopenicillin component of this series, first order kinetics should be statistically selected.

Multiple dose pharmacokinetic study of cicletanine in healthy volunteers.

Cicletanine hydrochloride, a furopyridine derivative, is a new type of antihypertensive drug. A pharmacokinetic study was performed in 8 non-patient subjects who were given 50 mg oral daily doses for 7 days. Cicletanine plasma levels were measured by HPLC. An open bicompartmental model was fitted to the experimental data using an extended non-linear regression method. Additionally plasma levels obtained after the first administration were used to determine pharmacokinetic parameters, which were considered as representative of a single dose administration. The results showed no significant differences between parameters estimated after the first dose and repeated dosing. Mean half-life values were 7.3 and 7.9 hours respectively. The mean peak and trough concentration values in the last interval studied were 1730 and 44 ng/mL respectively. The accumulation index was negligible (1.15). The similarity in the values obtained after the first and repeated administration suggests that cicletanine displays a linear pharmacokinetic behaviour at a dose of 50 mg.

Lack of correlation between pharmacokinetic and pharmacodynamic behaviour of cyanamide in man. A preliminary report.

A pharmacokinetic and dynamic study of cyanamide, an inhibitor of aldehyde dehydrogenase (ALDH) used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in man after oral administrations. Cyanamide plasma levels were determined by a sensitive and specific high performance liquid chromatographic assay. Blood ALDH activity were estimated after oral administration of 0.3, 1 and 1.5 mg/kg of cyanamide. One i.v. administration of 1 mg/kg was performed in order to determine the absolute bioavailability and the main pharmacokinetic parameters. Elimination half life and total plasma clearance values were 51.7 8.8 min and 14.4 2.7 mL/kg/min respectively. After oral administrations of 0.3, 1 and 1.5 mg/kg a rapid absorption rate was estimated with a Tmax values range of 10.5 to 15.5 min. The extent of absorption was not complete, oral bioavailability being 53%, 70% and 81% respectively. The presence of a first pass-effect is suggested. The inhibitory activity of cyanamide on blood ALDH reached the maximum value 4 h after its administration and decreased progressively throughout six days period. The cyanamide plasma levels time course did not correlated with the pharmacodynamic time course responses.

Comparative study "in vitro" of transdermal absorption of a series of antiemetic drugs.

The "in vitro" transdermal absorption characteristics of various antiemetic drugs (Alizapride, Bromopride, Clebopride, Domperidone, Metoclopramide, Metopimazine) were studied. Franz diffusion glass cells were used. The skin of hairless rat was used as a permeation membrane. The following parameters were evaluated for each drug: Permeation constant (Kp), lag time (T1), and flux (J). A comparative study of permeation characteristics of the assayed drugs was carried out. Their potential use as transdermal dosage forme was also studied. Based on the results, Bromopride and Clebopride have showed the best "in vitro" permeation profile to be used by transdermal administration.

Reduction of oral bioavailability of paracetamol by tolmetin in rat.

The pharmacokinetics of paracetamol alone and coadministered with tolmetin were studied in male Wistar rats. Open pharmacokinetic model of one and two compartments were fitted to experimental average plasma levels of paracetamol. Simultaneously fittings (intravenous and oral curves showed significant statistical differences for bioavailability estimated parameters (AUCev, F and K01). Also significant statistical differences were found for alfa, beta, K21 and Vd(ss) estimated parameters. Oral paracetamol bioavailability reduction (24%) was observed by coadministration of tolmetin in the rat. Since AUCiv and plasma clearance of paracetamol remained unchanged after intravenous coadministration, may be suggested that absorption process seems responsible of paracetamol bioavailability reduction.

Study of the release process of drugs: suppositories of paracetamol.

The release process of paracetamol, formulated in suppositories, prepared with four different Suppocire masses (AM, AML, AS2X and AP), having different hydrophilia, supplied by Gattefossé, was investigated. The release study of paracetamol was carried out "in vitro" by means of the Dissotest apparatus (Sotax), built on the base of the flow-through method. The assay conditions were: pH 7.4 and flow rate of 20 ml/min. The release process was evaluated using the following amodelistic parameters: the mean dissolution time (MDT), the variance of dissolution time (VDT), the dissolution efficiency (DE) and the maximum amount dissolved determined experimentally (Qmax). The amodelistic parameters, after their statistical analysis by the Kruskal-Wallis test, followed by the comparison between data pairs by the Mann-Whitney "U" test, proved that there are significant differences (p less than 0.05), with the exception of Qmax, between the four masses tested. This study shows that the masses which have a surfactant in their composition (AS2X and AP) offer a better release of paracetamol than those which have no surfactant (AM and AML).