Improvement and characterization of oral absorption behavior of clofazimine by SNEDDS: Quantitative evaluation of extensive lymphatic transport.

Clofazimine, an anti-leprosy drug, has been anticipated for a candidate to treat tuberculosis, cryptosporidiosis, and coronavirus infection, but its low oral bioavailability is considered a reason for its limited activity. In the current study, we have tried to improve the oral bioavailability of clofazimine by several SNEDDS formulations and characterized the absorption behavior from various aspects. Among four SNEDDS formulations prepared, SNEDDS A, prepared with castor oil as an oil component, provided the highest bioavailability (around 61%) and SNEDDS D, prepared with Capryol 90, gave the second highest bioavailability. SNEDDS A formed the finest nanoparticles, which were maintained under gastric and intestinal luminal conditions. The comparison in oral bioavailability between the SNEDDS formulation and its corresponding preformed nanoemulsion suggested that SNEDDS A would efficiently form nanoemulsion in the gastrointestinal tract after oral administration. AUC of mesenteric lymph node concentration was the highest for SNEDDS A, which would be one of the reasons for SNEDDS A to reveal the highest oral bioavailability. A cycloheximide-treated oral absorption study and single-pass perfusion study by utilizing a vascular-luminal perfused small intestine-liver preparation clearly indicated that over 90% of clofazimine absorbed to systemic circulation should be derived from lymphatic transport for both SNEDDS A and D. Furthermore, the fraction of dose absorbed was around 65% for SNEDDS D, but SNEDDS A achieved around 94%, indicating the excellent performance of SNEDDS A.

Clofazimine broadly inhibits coronaviruses including SARS-CoV-2.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

Metabolism and interactions of antileprosy drugs.

Leprosy is a chronic infectious disease caused my Mycobacterium leprae that primarily affects peripheral nervous system and extremities and is prevalent in tropical countries. Treatment for leprosy with multidrug regimens is very effective compared to monotherapy especially in multibacillary cases. The three major antileprosy drugs currently in use are 4, 4'-diaminodiphenyl sulfone (DDS, dapsone), rifampicin, and clofazimine. During multidrug therapy, the potent antibiotic rifampicin induces the metabolism of dapsone, which results in decreased plasma half-life of dapsone and its metabolites. Furthermore, rifampicin induces its own metabolism and decreases its half-life during monotherapy. Rifampicin upregulates several hepatic microsomal drug-metabolizing enzymes, especially cytochrome P450 (CYP) family that in turn induce the metabolism of dapsone. Clofazimine lacks significant induction of any drug-metabolizing enzyme including CYP family and does not interact with dapsone metabolism. Rifampicin does not induce clofazimine metabolism during combination treatment. Administration of dapsone in the acetylated form (acedapsone) can release the drug slowly into circulation up to 75 days and could be useful for the effective treatment of paucibacillary cases along with rifampicin. This review summarizes the major aspects of antileprosy drug metabolism and drug interactions and the role of cytochrome P450 family of drug metabolizing enzymes, especially CYP3A4 during multidrug regimens for the treatment of leprosy.

Five-Stage Approach for a Systematic Screening and Development of Etravirine Amorphous Solid Dispersions by Hot-Melt Extrusion.

The aim of this study was to develop a fast, effective, and material sparing screening method to design amorphous solid dispersions (ASDs) of etravirine to drive more effectively the development process, leading to improved bioavailability (BA) and stability. A systematic step-by-step approach was followed by combining theoretical calculations with high-throughput screening (HTS) and software-assisted multivariate statistical analysis. The thermodynamic miscibility and interaction of the drug in several polymers were predicted using Hansen solubility parameters (δ). The selected polymers were evaluated by HTS, using solvent evaporation. Binary compositions were evaluated by their solubilization capacity and physical stability over 2 months. JMP 14.0 was used for multivariate statistical analysis using principal components analysis. Extrusion was performed in Thermo Scientific HAAKE MiniLab II, and extrudates were characterized by assay, related substances, dissolution, and physical state (polarized light microscopy (PLM), Raman spectroscopy, and X-ray powder diffraction (XRPD)). A short stability study was performed where milled extrudates were exposed to 25 °C/60%RH and 40 °C/75%RH for 3 months. Through thermodynamic predictions, five main polymers were selected. The HTS enabled the evaluation of 42 formulations for solubilization capacity and physical stability. The three most promising compositions were selected for hot-melt extrusion (HME) tests. In general, a good correlation was found among the results of theoretical predictions, HTS, and HME. Poly(vinylpyrrolidone) (PVP)-based formulations were shown to be easily extrudable, with low degradation and complete amorphicity, whereas in Soluplus, the drug was not miscible, leading to a high crystalline content. The drug release rate was improved more than two times with PVP, and the manufactured ASD was demonstrated to be stable physically and chemically. A fast and effective screening technique to develop stable ASDs for a poorly soluble drug was successfully developed as applied to etravirine. The given method is easy to use, requires a low amount of drug, and is fairly accurate in predicting the amorphization of the drug when formulated. The success of HME formulation development of etravirine was undoubtedly enhanced with this high-throughput tool, which led to the identification of extrudates with improved biopharmaceutical properties. The structural characterization performed by PLM, XRPD, and Raman spectroscopy demonstrated that the HME prototype was essentially amorphous. The unexpected stability at 40 °C/75%RH was correlated with the presence of molecular interaction characterized by Raman spectroscopy.

Systematic evaluation of the impact of solid-state polymorphism on the bioavailability of thalidomide.

Thalidomide (TLD) is used to treat erythema nodosum leprosum (ENL), multiple myeloma, aphthous ulceration and wasting syndrome in HIV patients. The API can be found in two crystalline habits known as α-TLD and ß-TLD. The saturation solubility (Cs) and the dissolution profiles under non-sink and sink conditions of both polymorphs were assessed. In addition, mini-capsules containing α-TLD or ß-TLD without excipients were orally given (10 mg/kg) to Wistar rats. An intravenous (i.v.) dose was also administrated (5 mg/kg). The Cs values for α-TLD and ß-TLD were not significantly different (α = 56.2 ±â€¯0.5 µg·mL-1; ß = 55.2 ±â€¯0.2 µg·mL-1). However, the dissolution profile of α-TLD presented the fastest rate and the largest extension of drug dissolution than that from ß-TLD (80% in 4 h versus 55% in 4 h). The α-TLD provided a more favorable pharmacokinetic than the ß-TLD (maximum plasma concentration - Cmax: 5.4 ±â€¯0.90 µg·mL-1versus 2.6 ±â€¯0.2 µg·mL-1; area under the curve of the concentration-time profile from time zero to infinity - AUC0-∞: 44.3 ±â€¯8.8 µg·h·mL-1versus 33.9 ±â€¯4.7 µg·h·mL-1; absolute bioavailability - F: 92.2 ±â€¯18.5% versus 70.5 ±â€¯9.9%, respectively). Drug suppliers and pharmaceutical companies should strictly control the technological processes involved in the TLD API synthesis as well as in the production of the pharmaceutical dosage form in order to guarantee the inter-batch homogeneity and therefore, product compliance.

Hansen solubility parameters (HSP) for prescreening formulation of solid lipid nanoparticles (SLN): in vitro testing of curcumin-loaded SLN in MCF-7 and BT-474 cell lines.

Curcumin, a phenolic compound from turmeric rhizome (Curcuma longa), has many interesting pharmacological effects, but shows very low aqueous solubility. Consequently, several drug delivery systems based on polymeric and lipid raw materials have been proposed to increase its bioavailability. Solid lipid nanoparticles (SLN), consisting of solid lipid matrix and a surfactant layer can load poorly water-soluble drugs, such as curcumin, deliver them at defined rates and enhance their intracellular uptake. In the present work, we demonstrate that, despite the drug's affinity to lipids frequently used in SLN production, the curcumin amount loaded in most SLN formulations may be too low to exhibit anticancer properties. The predictive curcumin solubility in solid lipids has been thoroughly analyzed by Hansen solubility parameters, in parallel with the lipid-screening solubility tests for a range of selected lipids. We identified the most suitable lipid materials for curcumin-loaded SLN, producing physicochemically stable particles with high encapsulation efficiency (>90%). Loading capacity of curcumin in SLN allowed preventing the cellular damage caused by cationic SLN on MCF-7 and BT-474 cells but was not sufficient to exhibit drug's anticancer properties. But curcumin-loaded SLN exhibited antioxidant properties, substantiating the conclusions that curcumin's effect in cancer cells is highly dose dependent.

Effect of rifampicin pretreatment on the oral bioavailability of domperidone in healthy human volunteers.

BACKGROUND: Increased exsorption of domperidone was observed from different parts of the small intestine of the rat after pretreatment with rifampicin by the everted sac method. Based on the in vitro studies the effect of rifampicin pretreatment on the pharmacokinetics of domperidone was investigated in eight healthy male volunteers. METHODS: After an overnight fast, 20 mg domperidone was administered to the volunteers, either alone or after 6 days pretreatment with a once daily dose of 600 mg rifampicin. Serum concentrations of domperidone were estimated by reverse phase HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program kinetica. RESULTS: Rifampicin pretreatment decreased Cmax, AUCo-∞, AUMC, MRT and t1/2 by 25.11%, 37.76%, 64.97%, 43.71% and 44.48%, respectively. This may be due to increased induction of cytochrome P450 enzymes and/or increased expression of P-glycoprotein. CONCLUSIONS: This interaction may have clinical significance when domperidone is co-administered with rifampicin in chronic treatment conditions, such as tuberculosis, leprosy and other infections of joints, bones, etc.

Application of carrier and plasticizer to improve the dissolution and bioavailability of poorly water-soluble baicalein by hot melt extrusion.

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel.

For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel. The combined use of Hansen solubility parameters and dissolution experiments resulted in the development of a solid dispersion formulation containing 1/11 w/w paclitaxel, 9/11 w/w polyvinylpyrrolidone (PVP) K30, and 1/11 w/w sodium lauryl sulfate (SLS). Analysis of the solid dispersion formulation by X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and modulated differential scanning calorimetry (mDSC) confirmed the amorphous nature of paclitaxel and the fine dispersion of paclitaxel in the matrix of PVP-K30 and SLS. Furthermore, in vitro tests showed a major increase in the apparent solubility and dissolution rate of paclitaxel. To test the clinical significance of these findings, the solid dispersion formulation of paclitaxel (ModraPac001 10mg capsule) was compared to the paclitaxel premix solution in four patients with advanced cancer. Although the mean systemic exposure to paclitaxel after oral administration of the solid dispersion formulation was slightly lower compared to the paclitaxel premix solution (190±63.1ng/mLh for vs. 247±100ng/mLh), the systemic exposure to paclitaxel is clinically relevant [1,2]. In addition to this, the favorable pharmaceutical characteristics, for example, neutral taste, dosing accuracy, and the 2-year ambient shelf life, make the ModraPac001 10mg capsule an attractive candidate for oral paclitaxel chemotherapy. Currently, the ModraPac001 formulation is applied in the first clinical trial with oral LDM chemotherapy of paclitaxel.

Identificação e propriedades físico-químicas da clorofilina cúprica de sódio e da clorina cúprica e6 / Identification and physicochemical properties of sodium copper chloruphyllin and copper chlorin e6

A clorofilina cúprica de sódio (CuChl) é um corante semissintético derivado da clorofila. Quimicamente é constituído de diversas clorinas, em especial a clorina cúprica e4 (CuCe4), a clorina cúprica e6 (CuCe6), e possíveis clorinas e porfirinas não cúpricas em proporções variáveis. Além do seu uso como corante alimentar, são atribuídas atividades biológicas à CuChl, tais como, antimutagênica, anticarcinogênica e antioxidante. Em decorrência destes potenciais efeitos benéficos, sua comercialização sob a forma de suplementos é crescente. Todavia, curiosamente, informações sobre a absorção e biodisponibilidade da CuChl são escassas. Além disso, até o momento nenhum estudo avaliou o impacto da composição da CuChl em sua bioatividade e eficácia. Assim, o presente estudo teve como objetivo identificar e caracterizar quimicamente duas amostras de CuChl (Sigma® e Chr. Hansen®) e o padrão de CuCe6 (Frontier Scientific®). Para tanto, empregou-se técnicas cromatográficas e espectrofotométricas, determinou-se a lipofilicidade em modelos miméticos de membrana, cinética de degradação e avaliou-se a interação CuCe6/BSA. A análise elementar da CuChl resultou em teores de cobre total inferiores aos recomendados pela United States Pharmacopeia (U.S.P.). Os elementos (CHN) e a razão Cu/N não foram coerentes com os valores teóricos da molécula de CuChl. Apenas uma amostra de CuChl apresentou razão Soret/Q dentro dos valores preconizados pela U.S.P. A titulação base-ácido da CuCe6 revelou dois valores de pkas (10,62 e 6,41) que foram similares para as amostras de CuChl. A determinação de log P da CuCe6 mostrou que a hidrofobicidade é máxima em pH 3 (log P = 1,49±0,09) e sua hidrofilicidade ocorre em pHs > 7. Esse comportamento foi confirmado nos ensaios de incorporação em lipossomas em função do pH. A degradação térmica da CuChl (25 a 95 °C) avaliada por HPLC foi drástica a partir de 75 °C. A energia necessária para que ocorra a degradação da CuChl e CuCe6 é Ea = 16,1 e 9,3kcal/mol, respectivamente. A meia-vida a 35 °C é de 6 horas para a CuChl e 2 horas e meia para a CuCe6. A separação mais eficiente dos componentes da CuChl por HPLC foi conseguida utilizando coluna C30 e a identificação dos principais constituintes CuCe6, CuCe4 e a clorina cúprica p6 (CuCp6), ocorreu por HPLC/MSMS. No estudo da ligação entre CuCe6 e proteína BSA foram obtidos os valores de KD = 0,38 ± 0,07 µM, KA = 3,3 ± 0,28 x 106 M-1 e número de sítios de ligação ~1 (N = 0,75 ± 0,09), indicativo de alta afinidade entre a clorina e a proteína. Assim, o comportamento químico dos principais componentes da CuChl e sua interação com os componentes do soro tornaram inviáveis a identificação e quantificação destas moléculas em ensaios in vivo. Os resultados aqui apresentados servem de subsídio para o desenvolvimento de outras pesquisas que visem o estudo específico da associação e dissociação da CuChl em material biológico

Sodium copper chlorophyllin (CuChl) is a semisynthetic derivative of chlorophyll dye. It is composed chemically by several chlorins, especially copper chlorin e4 (CuCe4), copper chlorin e6 (CuCe6), and possible others no copper porphyrins and chlorins in different proportions. In addition to its use as a food coloring, CuChl may have interesting biological effects as antimutagenic, anticarcinogenic and antioxidant. Because of these potential benefits, its use as a dietary supplement is increasing. However, information on the absorption and bioavailability of CuChl is scarce. Furthermore, no studies have evaluated the impact of CuChl composition in its bioactivity and efficacy. Thus, the present study aimed to identify and chemically characterize two samples of CuChl (Sigma® and Hansen®) and the standard of CuCe6 (Frontier Scientific®). Chromatographic and spectrometric techniques as well as mimetics models membrane were used. The CuCe6/BSA interaction was also evaluated. The elemental analysis of CuChl showed that the total copper content of it was smaller that the one recommended by United States Pharmacopeia (USP). The elements (CHN) and the ratio Cu / N were not consistent with the theoretical values of the molecule CuChl. Only one CuChl sample showed Soret / Q ratio within the range recommended by USP. The acid-base titration of CuCe6 revealed two pKas values (10.62 and 6.41), which were similar for CuChl samples. The log P determination of CuCe6 showed that its hydrophobicity is maximal at pH 3 (log P = 1.49 ± 0.09) and its hydrophilicity occurs at pH> 7. These results were confirmed using the incorporation into liposomes assay in function of pH. Using HPLC, it was observed that thermal degradation of CuChl (25 to 95 °C) hardly occurred from 75 °C. The energy necessary for CuChl and CuCe6 degradation is Ea = 16.1 and 9.3 kcal/mol, respectively. The half-life at 35°C for CuChl and CuCe6 is 6 hours and 2 ½ hours, respectively. A more efficient separation of the CuChl components by HPLC was achieved using a C30 column while its major constituents CuCe6, CuCe4 and copper chlorin p6 (CuCp6) were identified by HPLC / MS-MS. In binding analysis of CuCe6 and BSA, it was observed KD = 0.38 ± 0.07 mM, KA = 3.3 ± 0.28 x 106 M-1, and number of binding sites ~ 1 (N = 0.75 ± .09), indicating high affinity between BSA and chlorine. Thus, due to the chemical characteristics of the main components of CuChl and their interaction with serum components the identification and quantification of these molecules in vivo is unviable. Future studies should investigate the association and dissociation of CuChl in biological samples

Development and characterization of a new oral dapsone nanoemulsion system: permeability and in silico bioavailability studies.

BACKGROUND: Dapsone is described as being active against Mycobacterium leprae, hence its role in the treatment of leprosy and related pathologies. Despite its therapeutic potential, the low solubility of dapsone in water results in low bioavailability and high microbial resistance. Nanoemulsions are pharmaceutical delivery systems derived from micellar solutions with a good capacity for improving absorption. The aim of this work was to develop and compare the permeability of a series of dapsone nanoemulsions in Caco-2 cell culture against that of effective permeability in the human body simulated using Gastroplus™ software. METHODS AND RESULTS: The release profiles of the dapsone nanoemulsions using different combinations of surfactants and cosolvent showed a higher dissolution rate in simulated gastric and enteric fluid than did the dispersed dapsone powder. The drug release kinetics were consistent with a Higuchi model. CONCLUSION: This comparison of dapsone permeability in Caco-2 cells with effective permeability in the human body simulated by Gastroplus showed a good correlation and indicates potential improvement in the biodisponibility of dapsone using this new system.

Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction.

Systemic and oral clearances of alfentanil (ALF) are in vivo probes for hepatic and first-pass cytochrome P450 (CYP) 3A. Both ALF single-point plasma concentrations and miosis are surrogates for area under the concentration-time curve (AUC) and clearance and are minimal and noninvasive CYP3A probes. This investigation determined ALF sensitivity for detecting graded CYP3A induction and compared it with that of midazolam (MDZ). Twelve volunteers (sequential crossover) received 0, 5, 10, 25, or 75 mg oral rifampin for 5 days. MDZ and ALF were given intravenously and orally on sequential days. Dark-adapted pupil diameter was measured with blood sampling. Graded rifampin decreased plasma MDZ AUCs to 83, 76, 62, and 59% (intravenous (i.v.)) and 78, 66, 39, and 24% (oral) of control. Hepatic and first-pass CYP3A induction were detected comparably by plasma MDZ and ALF AUCs. Single ALF concentrations detected all CYP3A induction, whereas MDZ was less sensitive. ALF miosis detected induction of first-pass but not hepatic CYP3A.

Biowaiver monographs for immediate release solid oral dosage forms: rifampicin.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing rifampicin as the only Active Pharmaceutical Ingredient (API) are reviewed. Rifampicin's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. Solubility and absolute BA data indicate that rifampicin is a BCS Class II drug. Of special concern for biowaiving is that many reports of failure of IR solid oral dosage forms of rifampicin to meet BE have been published and the reasons for these failures are yet insufficiently understood. Moreover, no reports were identified in which in vitro dissolution was shown to be predictive of nonequivalence among products. Therefore, a biowaiver based approval of rifampicin containing IR solid oral dosage forms cannot be recommended for either new multisource drug products or for major scale-up and postapproval changes (variations) to existing drug products.

Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases.

Zinc is required for multiple cellular tasks, and especially the immune system depends on a sufficient availability of this essential trace element. During the last decades, many studies attempted to affect the outcome of various diseases by zinc supplementation. These efforts either aimed at supporting immunity by zinc administration or at correcting a loss of zinc secondary to the disease to restore the zinc-dependent functions of the immune system. This review aims to summarize the respective findings and to discuss possible molecular mechanisms by which zinc could influence viral, bacterial, and parasitic infections, autoimmune diseases, and the response to vaccination. Zinc supplementation in diseases such as diarrhea, chronic hepatitis C, shigellosis, leprosy, tuberculosis, pneumonia, acute lower respiratory infection, and leishmaniasis seems beneficial. In contrast, the results for the common cold and malaria are still not conclusive, and zinc was ineffective in most vaccination and rheumatoid arthritis studies. For AIDS and type 1 diabetes, zinc supplementation may even be a risk factor for increased mortality or deterioration of the glucose metabolism, respectively. In these cases, zinc supplementation should be used with care and limited to clearly zinc-deficient individuals.

Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid.

BACKGROUND: Clofazimine is potentially useful for the treatment of disease due to multidrug resistant Mycobacterium tuberculosis, as well as leprosy and certain chronic skin diseases. Its pharmacokinetics have been incompletely characterized. This study was conducted to explore issues relating to bioavailability in the presence of food, orange juice, and antacid. METHODS: A 5 drug regimen consisting of clofazimine, cycloserine, ethionamide, para-aminosalicyclic acid, and pyridoxime was administered to healthy subjects four times using a four period cross-over design with two weeks washout between treatments. Subjects also received orange juice, a high fat meal, aluminum/magnesium antacid, or only water in random order with the drug regimen. The pharmacokinetics of clofazimine were assessed using individual- and population-based methods and relative bioavailability compared to fasting administration was determined. RESULTS: Clofazimine exhibited a sometimes prolonged and variable lag-time and considerable variability in plasma concentrations. From the population analysis (one-compartment model), the mean oral clearance was 76.7 l/h (CV=74.2%) and mean apparent volume of distribution was 1470 l (CV=36.3%). The first-order absorption rate constant ranged from 0.716 to 1.33 h(-1) (pooled CV=61.7%). Residual (proportional) error was 49.1%. Estimates of bioavailability compared to fasting administration were 145% (90% CI, 107-183%) for administration with high fat food, 82.0% (63.2-101%) for administration with orange juice, and 78.5% (55.1-102%) for administration with antacid. CONCLUSION: Administration of clofazimine with a high fat meal provides the greatest bioavailability, however, bioavailability is associated with high inter- and intra-subject variability. Both orange juice and aluminum-magnesium antacid produced a reduction in mean bioavailability of clofazimine.

Release mechanism of insulin encapsulated in trehalose ester derivative microparticles delivered via inhalation.

The aim of this study was to evaluate properties of amorphous oligosaccharide ester derivative (OED) microparticles in order to determine drug release mechanisms in the lung. Trehalose OEDs with a wide range of properties were synthesised using conventional methods. The interaction of spray dried amorphous microparticles (2-3 microm) with water was investigated using attenuated total reflectance Fourier transform infra-red spectroscopy (ATR-FTIR) and dynamic vapour sorption (DVS). The in vivo performance of insulin/OED microparticles was assessed using a modified Higuchi kinetic model. A modified Hansen solvent parameter approach was used to analyse the interactions with water and in vivo trends. In water or high humidity, OED powders absorb water, lose relaxation energy and crystallise. The delay of the onset of crystallisation depends on the OED and the amount of water present. Crystallisation follows first order Arrhenius kinetics and release of insulin from OED microparticles closely matches the degree of crystallisation. The induction period depends on dispersive interactions between the OED and water while crystallisation is governed by polarity and hydrogen bonding. Drug release from OED microparticles is, therefore, controlled by crystallisation of the matrix on contact with water. The pulmonary environment was found to resemble one of high humidity rather than a liquid medium.

Influence of rifampicin pretreatment on the pharmacokinetics of celecoxib in healthy male volunteers.

The effect of rifampicin pretreatment on the pharmacokinetics of celecoxib was investigated in 12 healthy male human volunteers. After an overnight fast, celecoxib 200 mg was administered to the volunteers, either alone or after 5 days pretreatment with once daily dose of 600 mg rifampicin. Serum concentrations of celecoxib were estimated by reverse phase HPLC. Pharmacokinetic parameters were determined based on non-compartmental model analysis using the computer program KINETICA. A significant difference was observed in AUC(0-1) (4531.28 +/- 2147 vs 1629.1 +/- 1006 ng x h x ml(-1), p < 0.0001), AUC(0-infinity) (4632.42 +/- 2221.75 vs 1629.46 +/- 1012.61 ng x h x ml(-1), p = 0.0006), Cmax (544.89 +/- 273.91 vs 238.61 +/- 146.34 ng/ml, p = 0.04), t(1/2) (9.3 +/- 3.58 vs 4.0 +/- 1.43 h, p = 0.0317) and Cl/f (43.14 +/- 36.23 vs 122.85 +/- 95 l x h(-1), p < 0.0001) of celecoxib administered before and after rifampicin pretreatment. However, time to reach peak concentration, tmax (4 +/- 0.88 vs 4 +/- 0.83 h) and volume of distribution Vd/f (583 +/- 251 vs 710 +/- 690 l/kg) were not affected significantly. Rifampicin pretreatment reduced the AUC of celecoxib by 64% and increased the clearance by 185%. This may be due to increased metabolism of celecoxib due to the induction of cytochrome P4502C9 (CYP2C9) in liver. This interaction has a significant clinical relevance and may warrant dosage adjustment when celecoxib is co-administered with rifampicin in chronic treatment conditions, such as tuberculosis, leprosy and other infections of joints, bones, etc.

Antibiotics and oral contraceptives

With the exception of rifampin-like drugs, there is a lack of scientific evidence supporting the ability of commonly prescribed antibiotics, including all those routinely employed in outpatient dentistry, to either reduce blood levels and/or the effectiveness of oral contraceptives. To date, all clinical trials studying the effects of concomitant antibiotic therapy (with the exception of rifampin and rifabutin) have failed to demonstrate an interaction. Like all drugs, oral contraceptives are not 100 per cent effective with the failure rate in the typical United States population reported to be as high as 3 per cent. It is thus possible that the case reports of unintended pregnancies during antibiotic therapy may simply represent the normal failure rate of these drugs. Considering that both drug classes are prescribed frequently to women of childbearing potential, one would expect a much higher rate of oral contraceptive failure in this group of patients if a true drug:drug interaction existed. On the other hand, if the interaction does exist but is a relatively rare event, occurring in, say, 1 in 5000 women, clinical studies such as those described in this article would not detect the interaction. The pharmacokinetic studies of simultaneous antibiotic and oral contraceptive ingestion, and the retrospective studies of pregnancy rates among oral contraceptive users exposed to antibiotics, all suffer from one potential common weakness, i.e., their relatively small sample size. Sample sizes in the pharmacokinetic trials ranged from 7 to 24 participants, whereas the largest retrospective study of pregnancy rates still evaluated less than 800 total contraceptive users. Still, the incidence of such a rare interaction would not differ from the accepted normal failure rate of oral contraceptive therapy. The medico-legal ramifications of what looks like at best a rare interaction remains somewhat "murky." On one hand, we have medico-legal experts advising the profession to exercise caution and warn all oral contraceptive users of a potential reduction in efficacy during antibiotic therapy. These opinions are not evidence-based and rely heavily on one or two legal proceedings that cannot even be substantiated. On the other hand, there is one recently published legal proceeding in which the outcome was in favor of the oral surgeon. There is clearly...