Solid-state nanoparticle coated emulsions for encapsulation and improving the chemical stability of all-trans-retinol

Submicron oil-in-water (o/w) emulsions stabilised with conventional surfactants and silica nanoparticles were prepared and freeze-dried to obtain free-flowing powders with good redispersibility and a three-dimensional porous matrix structure. Solid-state emulsions were characterised for visual appearance, particle size distribution, zeta potential and reconstitution properties after freeze-drying with various sugars and at a range of sugar to oil ratios. Comparative degradation kinetics of all-trans-retinol from freeze-dried and liquid emulsions was investigated as a function of storage temperatures. Optimum stability was observed for silica-coated oleylamine emulsions at 4 °C in their wet state. The half-life of all-trans-retinol was 25.66 and 22.08 weeks for silica incorporation from the oil and water phases respectively. This was ∼4 times higher compared to the equivalent solid-state emulsions with drug half-life of 6.18 and 6.06 weeks at 4 °C. Exceptionally, at a storage temperature of 40 °C, the chemical stability of the drug was 3 times higher in the solid-state compared to the wet emulsions which confirmed that freeze-drying is a promising approach to improve the chemical stability of water-labile compounds provided that the storage conditions are optimised.     

Effects of all-trans-retinoyl-β-d-glucuronide and all-trans-retinoic acid on chondrogenesis and retinoid metabolism in mouse limb bud mesenchymal cells in vitro

Retinoids, derivatives of vitamin A, are essential for many vertebrate functions. Furthermore, several drugs of this class of compounds are valuable in the treatment of certain forms of skin disorders and cancer. However, the therapeutic application of retinoids is limited by their teratogenic potency. The limbs are important sites of retinoid-induced malformations in rodents. Therefore, organoid cultures of limb bud mesenchymal cells have been established for screening of the teratogenic potency of retinoids. We have now applied this system to compare the effects of all-trans-retinoyl-β-d-glucuronide (all-trans-RAG) with those of all-trans-retinoic acid (all-trans-RA) on chondrogenesis, as assessed by the Alcian blue binding assay and by electron microscopic evaluation including quantitative morphometric analysis. First data of retinoid toxicokinetics in the culture media as well as retinoid concentrations in the cultured mesenchymal limb bud cells were established. While all-trans-RA inhibited chondrogenesis at 10⁻⁷ M by ca. 50%, tenfold higher concentrations of all-trans-RAG were necessary to obtain the same effect. This difference reflects the ratio of RA isomers which were found in the medium after incubation with either all-trans-RAG or all-trans-RA. A pulse experiment (10⁻⁵ M all-trans-RAG or all-trans-RA for the first 2 h of a 6-day incubation period) demonstrated inhibition of chondrogenesis with all-trans-RA, but not with all-trans-RAG. The data indicate that RAG inhibits chondrogenesis upon hydrolysis to RA. Surprisingly, the rather polar RAG isoforms were extensively accumulated in the limb bud mesenchymal cells when compared to the medium. Both all-trans-RAG and all-trans-RA also induced a large increase of retinyl ester concentrations in the chondrocytes compared to vehicle-treated cells. This finding further supports a recent suggestion that RA regulates retinol metabolism via feedback inhibition of retinol oxidation and stimulation of the esterification of retinol. Received: 2 August 1995 / Accepted: 19 July 1996     

Effect of <Emphasis Type="Italic">MDR1</Emphasis> C3435T polymorphism on lansoprazole in healthy Japanese subjects

Background and aims  The effect of multidrug resistance transporter gene 1 (MDR1) on the bioavailability and kinetics of several substrates has not yet been fully elucidated. We evaluated the influence of MDR1 C3435T polymorphism on the pharmacokinetics and pharmacodynamics of lansoprazole in Japanese subjects. Methods  Fifteen healthy volunteers with the rapid extensive metabolizer genotype of CYP2C19 were classified into three MDR1 C3435T genotype groups: C/C (n = 5), C/T (n = 5), and T/T (n = 5). Lansoprazole 30 mg was administered orally for 15 days. The intragastric pH and plasma lansoprazole levels were determined on days 1 and 15. Results  On day 1, the mean C_max of lansoprazole in the T/T group was significantly higher than that in the C/C or C/T groups (T/T 1,248, C/C 618, C/T 607 ng/ml; P = 0.038). On day 15, similar MDR1 genotype-dependent differences were observed in the C_max of lansoprazole, although smaller than the differences observed on day 1. In contrast, the intragastric pH attained after lansoprazole administration did not differ among MDR1 genotype groups on either day 1 or day 15. Conclusion  Although the sample size was small, our study demonstrated that the MDR1 C3435T polymorphism influenced the pharmacokinetics, but not the pharmacodynamics (i.e., intragastric pH), of lansoprazole in rapid metabolizers of CYP2C19.     

Cytotoxicity of Paclitaxel Incorporated in PLGA Nanoparticles on Hypoxic Human Tumor Cells

Purpose  The aim of this work was to prepare paclitaxel-loaded PLGA nanoparticles and determine cytotoxicity of released paclitaxel for two hypoxic human tumor cell lines: breast carcinoma (MCF-7) and carcinoma cervicis (HeLa). Methods  Poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles containing paclitaxel were prepared by o/w emulsification-solvent evaporation method. Physicochemical characteristics of nanoparticles were studied. Cellular uptake of nanoparticles was evaluated by transmission electronic microscopy and fluorescence microscopy. Flow cytometry quantified the number of cells held in G₂/M phase. Cell viability was determined by the ability of single cell to form colonies. Biodistribution of nanoparticles in mice was evaluated by fluorescence microscopy. Results  The nanoparticles were spherical with average diameter 318 ± 5.1 nm. The encapsulation efficiency was 88.52%. The drug release profile in vitro exhibited a biphasic pattern. Cellular uptake was observed. Co-culture of tumor cells with paclitaxel-loaded nanoparticles demonstrated that released paclitaxel retained its bioactivity to block cells in G₂/M phase. Paclitaxel-loaded nanoparticles exhibited cytotoxic effect on both hypoxic MCF-7 and HeLa cells and its cytotoxicity was more significant than that of free paclitaxel. Fluorescent nanoparticles were mainly distributed to liver and spleen of mice. Conclusions  Paclitaxel-loaded PLGA nanoparticles may be considered a promising drug delivery system to eradicate hypoxic tumor cells. Cheng Jin and Ling Bai contributed equally to this work.     

Near Infrared Spectrometry for the Quantification of Human Dermal Absorption of Econazole Nitrate and Estradiol

Purpose The purpose of this study was to demonstrate the use of near-infrared (NIR) spectrometry for the in vitro quantification of econazole nitrate (EN) and estradiol (EST) in human skin.Methods NIR spectra were collected from EN and EST powders to verify the presence of NIR chromophores. One percent EN cream, a saturated solution of EN, or 0.25% EST solution was applied to human skin. NIR spectra were collected and one-point net analyte signal (NAS) multivariate calibration was used to predict the drug concentrations. NIR results were validated against known skin concentrations measured by high-pressure liquid chromatography (HPLC) analysis of solvent extracts.Results NIR spectroscopy measured dermal absorption from saturated solutions of EN on human skin with an r² = 0.990, standard error of estimation (SEE) = 2.46%, and a standard error of performance (SEP) = 3.55%, EN cream on skin with an r² = 0.987, SEE = 2.30%, and SEP = 2.66%, and 0.25% solutions of EST on skin with an r² = 0.987, SEE = 3.30%, and SEP = 5.66%. Despite low permeation amounts of both drugs through the stratum corneum into human tissue, the NIR signal-to-noise ratio was greater than three, even for the lowest concentrations.Conclusion NIR analyses paralleled the results obtained from HPLC, and thus could serve as a viable alternative for measuring the topical bioavailability/bioequivalence of different EN and EST formulations. Because these experiments were conducted in human tissue, this research suggests an all-optical in vivo method of measurement for dermal absorption could be developed.     

Safety studies conducted on high-purity trans-resveratrol in experimental animals

trans-Resveratrol is a naturally occurring polyphenolic compound found in a variety of foods, but predominantly in grapes. Safety studies were conducted on high-purity trans-resveratrol (Resvida™), including skin and eye irritation, dermal sensitization, subchronic and reproductive toxicity, genotoxicity, and absorption, metabolism and excretion. Resvida™ was non-irritating to skin and eyes and non-sensitizing. It was non-mutagenic in a bacterial reverse mutation assay in Salmonella typhimurium and Escherichia coli, but exhibited clastogenic activity in a chromosomal aberration test in human lymphocytes. However, in an in vivo bone marrow micronucleus test in rats, Resvida™ was non-genotoxic. In a 28-day study, Resvida™ caused no adverse effects in rats at 50, 150 and 500 mg/kg bw/day. Similarly, in a 90-day study, Resvida™ did not cause any adverse effects in rats at up to 700 mg/kg bw/day; the highest dose tested. Resvida™ did not induce any adverse reproductive effects in an embryo–fetal toxicity study in rats at a dose of 750 mg/kg bw/day. Also, in vitro and in vivo absorption, metabolism, and excretion studies in Caco-2 cells, rat primary hepatocytes and male and female rats (in vivo) show that Resvida™ is readily absorbed, metabolized and excreted. These studies provide evidence that Resvida™ is well tolerated and non-toxic.     

Identification of the Promoter of Human Carbonyl Reductase 3 (<Emphasis Type="BoldItalic">CBR3</Emphasis>) and Impact of Common Promoter Polymorphisms on Hepatic <Emphasis Type="BoldItalic">CBR3</Emphasis> mRNA Expression

Purpose  Recent studies suggest that polymorphisms in human carbonyl reductase 3 (CBR3) influence the pharmacodynamics of doxorubicin. First, we sought to identify the promoter of CBR3. Next, we examined whether two CBR3 promoter polymorphisms (CBR3 -725T>C and CBR3 -326T>A) dictate promoter activity and hepatic CBR3 mRNA levels. Methods  The promoter activities of CBR3 reporter constructs were investigated in HepG2 and MCF-7 cells. CBR3 mRNA levels were documented in 95 liver samples from white (n = 62) and black (n = 33) donors. Genotype-phenotype correlation analyses were used to determine the impact of the CBR3 -725T>C and CBR3 -326T>A polymorphisms on hepatic CBR3 mRNA levels. Results  We identified the promoter of human CBR3. Liver samples from black donors showed higher relative CBR3 mRNA levels than samples from whites (CBR3 mRNA_blacks = 3.0 ± 3.1 relative fold vs. CBR3 mRNA_whites = 1.6 ± 1.5 relative fold, p = 0.021). The variant -725C and -326A alleles did not modify the gene reporter activities of engineered CBR3 promoter constructs. In line, hepatic CBR3 mRNA levels were not associated with CBR3 -725T>C and CBR3 -326T>A genotype status. Conclusions  These studies provide the first insights into the regulation and variable hepatic expression of polymorphic CBR3.     

Interethnic differences of <Emphasis Type="Italic">PEPT2</Emphasis> (<Emphasis Type="Italic">SLC15A2</Emphasis>) polymorphism distribution and associations with cephalexin pharmacokinetics in healthy Asian subjects

Objectives  The aims of this study were to characterize the population frequency of PEPT2 (SLC15A2) polymorphic variants in three Asian ethnic populations, namely Chinese, Malay and Asian Indian, and to investigate the associations of ethnicity (Chinese vs. Asian Indian), PEPT2 haplotype and cephalexin pharmacokinetics in healthy Asian subjects. Methods   PEPT2 polymorphisms were screened from a cohort of 96 Chinese, 96 Malay and 96 Asian Indian subjects. Cephalexin (1000 mg, orally) pharmacokinetics was characterized in an additional 15 Chinese and 15 Asian Indian healthy subjects. These 30 subjects were subsequently genotyped for their PEPT2 polymorphisms. Results  In total, ten common single nucleotide polymorphisms (SNPs) were detected in the three populations, forming two PEPT2 haplotypes. There were significant ethnic differences in PEPT2 haplotype distribution: the frequencies of the *1 and *2 alleles were 0.307 and 0.693 in the Chinese population, 0.495 and 0.505 in the Malay population and 0.729 and 0.271 in Asian Indian population, respectively. The C _max of cephalexin was significantly lower in the Chinese (29.80 ± 4.09 μg ml⁻¹) population than in the Asian Indian one (33.29 ± 4.97 μg ml⁻¹; P = 0.045). This difference could be explained by the higher average body weight of the Chinese population. There was no other significant difference in cephalexin pharmacokinetics between either ethnic or PEPT2 genotype groups. Conclusion   PEPT2 polymorphism distributions differ significantly between Chinese, Malay and Asian Indian populations. However, cephalexin pharmacokinetics is not meaningfully different between Chinese and Asian Indians. The association between the PEPT2 haplotype and cephalexin pharmacokinetics could not be confirmed, and future studies under better controlled conditions are needed.     

Relative absorption and dermal loading of chemical substances: Consequences for risk assessment

Quantification of skin absorption is an essential step in reducing the uncertainty of dermal risk assessment. Data from literature indicate that the relative dermal absorption of substances is dependent on dermal loading. Therefore, an internal exposure calculated with absorption data determined at a dermal loading not comparable to the actual loading may lead to a wrong assessment of the actual health risk. To investigate the relationship between dermal loading and relative absorption in a quantitative manner, 138 dermal publicly available absorption experiments with 98 substances were evaluated (87 in vitro, 51 in vivo; molecular weight between 40 and 950, log P between −5 and 13), with dermal loading ranging mostly between 0.001 and 10 mg/cm². In 87 experiments (63%) an inverse relationship was observed between relative dermal absorption and dermal loading, with an average decrease of factor 33 ± 69. Known skin irritating and volatile substances less frequently showed an inverse relationship between dermal loading and relative absorption.     

Genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine in Japanese patients with panic disorder

Objective  The objective of this study was to evaluate genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine (PAX) in Japanese patients with panic disorder (PD). Method  Plasma concentration of PAX was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants were determined by polymerase chain reaction techniques. PD severity was assessed using the Panic and Agoraphobia Scale (PAS). Results  Multiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype, and comorbid physical illness were significant factors affecting the initial pharmacotherapeutic effect of PAX in PD and indicated that these factors accounted for 52.4% (R ² = 0.524) of the variability in the percent reduction in PAS score. The final model was described by the following equation (P = 0.001): percent reduction in PAS score (%) = 68.5 − 1.2 × [plasma concentration of PAX (ng/ml)] − 33.0 × (L/S = 1, S/S = 0) − 21.8 × (with comorbid physical illness = 1, without comorbid physical illness = 0). Conclusion  The high plasma concentration of PAX, the L/S genotype of 5-HTTLPR, and comorbid physical illness might be associated with a poor response to the initial phase of pharmacotherapy of PD with PAX.     

Impact of CYP3A5 and CYP3A4 gene polymorphisms on dose requirement of calcineurin inhibitors, cyclosporine and tacrolimus, in renal allograft recipients of North India

The present study investigated pharmacogenetic associations of common cytochrome P450 3A (CYP3A5 and CYP3A4) polymorphisms with dose requirements of calcineurin inhibitors, cyclosporine (CsA) and tacrolimus (Tac) in renal transplant recipients of North India. Two hundred twenty four patients on CsA and 73 patients on Tac-based immunosuppression regimen were genotyped for CYP3A5*3 (6986A>G) and CYP3A4*1B (-290A>G) and correlated with CsA/Tac dose requirement (mg/kg/day) and dose-adjusted CsA (C₂)/Tac (T ₀) blood levels (concentration/dose ratio) at 1 month and 3 months posttransplantation. The dose-adjusted levels were significantly lower in CYP3A5 expressers for CsA (p = 0.037; 3 months) and Tac (p < 0.001; 1 month and p < 0.001; 3 months) compared to the non-expressers, suggesting that for a given dose their CsA/Tac blood concentration is lower. The CYP3A5 non-expresser genotype was associated with reduced risk for allograft rejection (HR-0.18, 95% CI 0.03–0.99). No influence of CYP3A4*1B on CsA/Tac pharmacokinetics was observed. CYP3A5 expressers were associated with significantly lower dose-adjusted CsA/Tac concentrations and higher allograft rejection episodes in patients on Tac therapy.     

Serum concentrations of sertraline and N-desmethyl sertraline in relation to CYP2C19 genotype in psychiatric patients

Objective  To investigate the impact of CYP2C19 genotype on serum concentrations of sertraline and N-desmethyl sertraline in psychiatric patients. Methods  Patients treated with sertraline (n = 121) were divided into six subgroups according to CYP2C19 genotype: CYP2C19*17/*17, CYP2C19*1/*17, CYP2C19*1/*1, CYP2C19*17/def, CYP2C19*1/def and CYP2C19def/def (def = allele encoding defective CYP2C19 metabolism, i.e. *2 and *3). Dose-adjusted serum concentrations were compared by linear mixed model analyses using the CYP2C19*1/*1 subgroup as reference. Results  Subgroups carrying one or two alleles encoding defective CYP2C19 metabolism achieved significantly higher mean dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline compared to the CYP2C19*1/*1 subgroup (P < 0.05). The effect of CYP2C19 genotype was expressed as 3.2-fold (sertraline) and 4.5-fold (N-desmethyl sertraline) higher dose-adjusted serum concentrations in the CYP2C19def/def subgroup compared to the CYP2C19*1/*1 subgroup (P < 0.01). The CYP2C19*17 allele had no influence on the dose-adjusted serum concentrations of sertraline and N-desmethyl sertraline. Conclusion  The significantly higher serum concentrations associated with alleles encoding defective CYP2C19 metabolism might be of relevance for the clinical outcome of sertraline treatment.     

Pharmacogenomics of CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and MDR1 in Vietnam

Aim  The aim of this study was to obtain pharmacogenetic data in a Vietnamese population on genes coding for proteins involved in the elimination of drugs currently used for the treatment of malaria and human immunodeficiency virus/acquired immunodeficiency syndrome. Method  The main polymorphisms on the cytochrome P450 (CYP) genes, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4 and CYP3A5, and the multi-drug resistance 1 gene (MDR1) were genotyped in 78 healthy Vietnamese subjects. Pharmacokinetic metrics were available for CYP2A6 (coumarin), CYP2C19 (mephenytoin), CYP2D6 (metoprolol) and CYP3As (midazolam), allowing correlations with the determined genotype. Results  In the CYP2 family, we detected alleles CYP2A6*4 (12%) and *5 (15%); CYP2B6*4 (8%), *6 (27%); CYP2C19*2 (31%) and *3 (6%); CYP2D6*4, *5, *10 (1, 8 and 44%, respectively). In the CYP3A family, CYP3A4*1B was detected at a low frequency (2%), whereas CYP3A5 *3 was detected at a frequency of 67%. The MDR1 3435T allele was present with a prevalence of 40%. Allele proportions in our cohort were compared with those reported for other Asian populations. CYP2C19 genotypes were associated to the S-4′-OH-mephenytoin/S-mephenytoin ratio quantified in plasma 4 h after intake of 100 mg mephenytoin. While CYP2D6 genotypes were partially reflected by the α-OH-metroprolol/metoprolol ratio in plasma 4 h after dosing, no correlation existed between midazolam plasma concentrations 4 h post-dose and CYP3A genotypes. Conclusions  The Vietnamese subjects of our study cohort presented allele prevalences in drug-metabolising enzymes that were generally comparable with those reported in other Asian populations. Deviations were found for CYP2A6*4 compared to a Chinese population (12 vs. 5%, respectively; P = 0.023), CYP2A6*5 compared with a Korean population (15 vs. <1%, respectively; P < 0.0001), a Malaysian population (1%; P < 0.0001) and a Chinese population (1%; P < 0.0001); CYP2B6*6 compared with a Korean population (27 vs. 12%; P = 0.002) and a Japanese population (16%; P = 0.021). Pharmacokinetic metrics versus genotype analysis reinforces the view that the predictive value of certain globally common variants (e.g. CYP2D6 single nucleotide polymorphisms) should be evaluated in a population-specific manner.     

Induction of cytochrome P450 2B6 activity by the herbal medicine baicalin as measured by bupropion hydroxylation

Purpose  This study investigated the effect of the herbal medicine baicalin on bupropion hydroxylation, a probe reaction for CYP2B6 activity related to different CYP2B6 genotype groups. Method  Seventeen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6, and 5 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with baicalin. Blood samples were taken up to 72 h after each bupropion dose, and pharmacokinetics profiles were determined on days 1 and 25 for bupropion and hydroxybupropion. Result  Baicalin administration increased hydroxybupropion maximum plasma concentration (C _max) by 73% [90% confidence interval (CI), 44–108%; P < 0.01] and the area under the concentration time curve extrapolated to infinity (AUC_0–∞) of hydroxybupropion by 87% (90% CI, 48–137%; P < 0.01), with no change in the elimination half-life of hydroxybupropion. Baicalin increased the AUC_0–∞ ratio of hydroxybupropion to bupropion by 63% (90% CI, 38–92%; P < 0.01). Conclusion  Baicalin significantly induced CYP2B6-catalyzed bupropion hydroxylation, and the effects of baicalin on other CYP2B6 substrate drugs deserve further investigation.     

Naringenin-Loaded Nanoparticles Improve the Physicochemical Properties and the Hepatoprotective Effects of Naringenin in Orally-Administered Rats with CCl<Subscript>4</Subscript>-Induced Acute Liver Failure

Purpose  A novel naringenin-loaded nanoparticles system (NARN) was developed to resolve the restricted bioavailability of naringenin (NAR) and to enhance its hepatoprotective effects in vivo on oral administration. Materials and methods  Physicochemical characterizations of NARN included assessment of particle size and morphology, powder X-ray diffraction, fourier transform infrared spectroscopy, and dissolution study. In addition, to evaluate its bioactivities and its oral treatment potential against liver injuries, we compared the hepatoprotective, antioxidant, and antiapoptotic effects of NARN and NAR on carbon tetrachloride (CCl₄)-induced hepatotoxicity in rats. Results  NARN had a significantly higher release rate than NAR and improved its solubility. NARN also exhibited more liver-protective effects compared to NAR with considerable reduction in liver function index and lipid peroxidation, in conjunction to a substantial increase in the levels of the antioxidant enzymes (P < 0.05). Moreover, NARN was able to significantly inhibit the activation of caspase-3, -8, and -9 signaling, whereas NAR only markedly inhibited caspase-3 and -9 (P < 0.05). Conclusion  NARN effectively improved the release of NAR which resulted in more hepatoprotective effects mediated by its antioxidant and antiapoptotic properties. These observations also suggest that nanoformulation can improve the free drug’s bioactivity on oral administration. Feng-Lin Yen and Tzu-Hui Wu contributed equally to this work.     

Oral absorption of propiverine solution and of the immediate and extended release dosage forms: influence of regioselective intestinal elimination

Purpose  The muscarine receptor antagonist propiverine in immediate release tablet form (IR) undergoes presystemic elimination mediated by CYP450 enzymes and intestinal efflux transporters. The aim of our study with propiverine IR and extended release (ER) was to determine whether propiverine disposition is dose linear, to compare the pharmacokinetics of propiverine in oral solution with IR and ER and to show how absorption rate is associated with bioavailability. Methods  The pharmacokinetics of propiverine administered as intravenous propiverine (15 mg), 10, 15, and 30 mg propiverine IR, an oral propiverine solution (15 mg) and 10, 15, 30, and 45 mg propiverine ER were measured in two randomized, controlled, single-dose, five-period, cross-over studies, with each case involving a study cohort of ten healthy Caucasian subjects. Results  Disposition of propiverine IR and ER was not dose-related. The bioavailability of ER was 64.5 ± 16.1% compared to 50.3 ± 13.4% (non-significant) after administration of the IR and propiverine solution (42.6 ± 14.8%, p < 0.05). The mean absorption time (MAT) of ER (14.2 ± 4.79 h) was significantly longer than that of the solution and IR (3.94 ± 4.14 and 0.38 ± 3.79 h, respectively; both p < 0.05). The bioavailability of propiverine was significantly correlated to the MAT (r = 0.521, p < 0.001). Renal excretion of the metabolite M-23 after propiverine ER administration (6.7 ± 2.7%) was significantly lower than that after administration of the oral solution (10 ± 2.2%) and of IR (9.8 ± 2.7%; both p < 0.05). Conclusions  The bioavailability of propiverine appears to be dependent on the intestinal site of dissolution and, consequently, on the extent of presystemic intestinal elimination.     

CYP2C19 genotype is associated with symptomatic recurrence of GERD during maintenance therapy with low-dose lansoprazole

Background/aims  Maintenance therapy of gastroesophageal reflux disease (GERD) is usually performed with a low dose of a proton-pump inhibitor (PPI). Because PPIs are metabolized by CYP2C19 in the liver, we investigated whether a patient’s CYP2C19 genotype was associated with symptomatic recurrence of GERD during maintenance therapy with a low dose of a PPI. Methods  We enrolled 124 patients with erosive GERD whose esophageal mucosal breaks were endoscopically proven to be cured after treatment with lansoprazole 30 mg/day for 8 weeks. When reflux symptoms occurred less than once per week, the dose of lansoprazole was decreased to 15 mg/day, but if symptoms then occurred more than once per week, it was restored to 30 mg/day. CYP2C19 genotypes were classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). Results  In 18 of 54 RMs, 28 of 56 IMs, and 8 of 14 PMs, the maintenance dose of lansoprazole was decreased to 15 mg/day, but in 16 (88.9%), 22 (78.6%), and 4 (50%), respectively, there was symptomatic recurrence of GERD and the dose was restored to 30 mg/day. The hazard ratios of symptomatic recurrence of GERD in IMs and PMs compared with RMs were 0.40 (95%CI: 0.19–0.87, P = 0.021) and 0.19 (95%CI: 0.05–0.69, P = 0.011). Conclusion  When the dose of lansoprazole is decreased, the RM genotype of CYP2C19 appears to be a risk factor for symptomatic recurrence of GERD. The CYP2C19 genotyping test would be useful for determining the optimal dose of a PPI for maintenance therapy of GERD. The abstract of the present study was presented at the annual meeting of the AGA held in San Diego, CA, in 2008.     

CYP2C9 genotypes and the quality of anticoagulation control with warfarin therapy among Brazilian patients

Objective To evaluate the impact of the two most common CYP2C9 variant alleles (*2 and *3) on the maintenance dose of warfarin and on the quality of anticoagulation control in Brazilians. Methods Patients (n = 103) initiated warfarin therapy with 5 mg/day (or 2.5 mg/day when over 80 years old). The international normalized ratio (INR) was targeted between 2 and 3, monitored every week until four consecutive adequate measures had been obtained, and then monthly. Serious hemorrhagic events were defined by the need for inpatient hospitalization. CYP2C9 genotyping was obtained by PCR-RFLP. Results The frequencies of CYP2C9*2 and CYP2C9*3 were 0.097 and 0.073, respectively, with genotypic distribution fitting Hardy-Weinberg equilibrium. CYP2C9 genotype was the only clinical feature associated with the risk of severe bleeding (one-sided P = 0.019, Fisher exact method), with an odds ratio of 4.8 (95% confidence interval of 1.4–16.6) for any variant genotype as compared to CYP2C9*1*1. Patients with either CYP2C9*2 or CYP2C9*3 were equally difficult to maintain in the INR target range, showing significantly (one-sided P = 0.038, Mann-Whitney U-test) reduced ratio of adequate INR measures (0.54 ± 0.2), when compared to CYP2C9*1*1 patients (0.63 ± 0.2). Patients with CYP2C9*3, but not CYP2C9*2, required significantly (one-sided P = 0.001, Mann-Whitney U-test) lower warfarin maintenance doses (3.1 ± 1.8 mg) than CYP2C9*1*1 patients (5.3 ± 2.1 mg). Conclusion Patients with either CYP2C9*2 or CYP2C9*3 show higher risk of over-anticoagulation compared to CYP2C9*1*1 subjects and could benefit from a reduction in the initial warfarin standard dose (e.g., to 2.5 mg/day).