Pharmacokinetics of oral salbutamol controlled-release in Asian patients with asthma

Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients.Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean C_max was 4.2 ng·ml^–1 and 7.7 ng·ml^–1 after 4 and 8 mg, respectively. In 5 patients the steady state mean C_max, C_min and t_max were 8.1 ng·ml^–1 and 4.7 ng·ml^–1 and 6 h for the 4 mg tablets and 14.1 ng·ml^–1 and 7.1 ng·ml^–1 and 4 h for the 8 mg tablets.It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.     

Determination of optimal vitamin D3 dosing regimens in HIV-infected paediatric patients using a population pharmacokinetic approach

AimsTo investigate 25-hydroxycholecalciferol [25(OH)D] population pharmacokinetics in children and adolescents, to establish factors that influence 25(OH)D pharmacokinetics and to assess different vitamin D₃ dosing schemes to reach sufficient 25(OH)D concentrations (>30 ng ml⁻¹).MethodsThis monocentric prospective study included 91 young HIV-infected patients aged 3 to 24 years. Patients received a 100 000 IU vitamin D₃ supplementation. A total of 171 25(OH)D concentrations were used to perform a population pharmacokinetic analysis.ResultsAt baseline 28% of patients had 25(OH)D concentrations below 10 ng ml⁻¹, 69% between 10 and 30 ng ml⁻¹ and 3% above 30 ng ml⁻¹. 25(OH)D pharmacokinetics were best described by a one compartment model with an additional production parameter reflecting the input from diet and sun exposure. The effects of skin phototype and bodyweight were significant on 25(OH)D production before any supplementation. The basal level was 27% lower in non-white skin phototype patients and was slightly decreased with bodyweight. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs. To obtain concentrations between 30 and 80 ng ml⁻¹, patients with baseline concentrations between 10 and 30 ng ml⁻¹ should receive 100 000 IU per 3 months. However, vitamin D deficient patients (<10 ng ml⁻¹) would need an intensive phase of 100 000 IU per 2 weeks (two times) followed 2 weeks later by a maintenance phase of 100 000 IU per 3 months.ConclusionsSkin phototype and bodyweight had an influence on the basal production of 25(OH)D. According to 25(OH)D baseline concentrations, dosing schemes to reach sufficient concentrations are proposed.     

Two-dimensional LC–MS/MS determination of antiretroviral drugs in rat serum and urine

A simple, rapid, reliable and highly sensitive on-line two-dimensional reversed-phase liquid chromatography–tandem mass spectrometric (2D-LC/MS/MS) method to determine antiretroviral drugs viz., abacavir (ABC), nevirapine (NVP) and indinavir (IDV) in rat serum and urine was developed and validated. The analytes were extracted on-line from rat serum and urine by a restricted access material (RAM) column and back-flushed into the reversed-phase C₁₈ column for separation by LC. Detection was carried out by ESI-MS/MS. The developed method showed good selectivity, accuracy and precision for quantification of the antiretroviral drugs in rat serum and urine. Quantification limits for abacavir and nevirapine were 4.0 ng ml⁻¹, whereas for indinavir 4.7 ng ml⁻¹. The calibration graphs were linear in the range of 4–50 ng ml⁻¹for abacavir, nevirapine and indinavir. The method was successfully applied to study the pharmacokinetics of antiretroviral in rats.     

Interaction of talinolol and sulfasalazine in the human gastrointestinal tract

Summary The absorption of talinolol (TA) 50 mg was investigated without and together with the co-administration of sulfasalazine (SASP) 4 g in 11 healthy young volunteers, in order to clarify gastrointestinal transit of TA.Without SASP, the t_max of TA was 2.8 h, C_max was 112 ng·ml^–1 and the half life was 12 h; the AUC_o-t was 958 ng·ml^–1·h.In the case of concomitant administration of SASP, TA was found only in serum from 3 individuals, with a C_max of 23 ng·ml^–1 and a mean AUC_o-t of 84 ng·ml^–1·h. TA was not detectable in 5 subjects and it was at the limit of detection (2 ng·ml^–1) in 3 subjects. Pharmacokinetic analysis was not possible in any of those individuals.The reason for the interaction appears to be the adsorption of TA by SASP. An interval of 2–3 h should elapse between giving SASP and other drugs.     

Pharmacokinetics and pharmacodynamics of thiazinamium in asthmatic patients

Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min^–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min^–1, and an elimination rate constant of 0.0044 min^–1. The corresponding estimates after i.m. administration were 0.324 l·min^–1, 34.1 l, 0.035 min^–1, and 0.0018 min^–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC₅₀ of 12.8 ng·ml^–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml^–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min^–1, with an EC₅₀ of 176 ng·ml^–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min^–1, 250 ng·ml^–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml^–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min^–1.     

Growth hormone-releasing activity of hexarelin in humans

Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH₂) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·g·kg^–1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (C_max) were 3.9, 26.9, 52.3, 55.0 ng·ml^–1 after 0, 0.5, 1 and 2 g·kg^–1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC_0–180) were 0.135, 1.412, 2.918 and 3.695 g·min·ml^–1. The theoretical maximum response (E_max) and the dose that produces half of the maximum response (ED₅₀) were estimated using logistic regression. The calculated ED₅₀ values were 0.50 and 0.64 g·kg^–1 for C_max and AUC_0–180, respectively. The corresponding E_maxs were 55.1 ng·ml^–1 and 3936 ng·min·ml^–1, thus indicating that the effect after the 2 g·kg^–1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.     

Effects of neonatal 17α‐ethinyloestradiol exposure on female‐paced mating behaviour in the rat

Correct perinatal oestrogen levels are critical for sexual differentiation. For example, perinatal exposure to oestrogen causes masculinization and defeminization of the brain in female rats and also induces delayed effects after maturation characterized by early onset of abnormal oestrus cycling. However, the mechanisms underlying the above effects of oestrogen remain to be fully determined. 17α‐ethinyloestradiol (EE), a common synthetic oestrogen widely used in oral contraceptives, binds specifically to oestrogen receptors. In this study, we demonstrated the effects of a single neonatal injection of high‐ or low‐dose EE on reproductive behaviours. Female rats within 24 h after birth were subcutaneously injected with sesame oil, EE (0.02, 2 mg kg⁻¹) and 17β‐oestradiol (E₂) (20 mg kg⁻¹). Between 11 and 15 weeks of age, sexual behaviour was tested twice in a paced mating situation. Latency to enter, lordosis and soliciting behaviour were recorded. Both high‐dose EE‐ and E₂‐treated females showed a significantly lower lordosis quotient, decreased soliciting behaviours, increased rejection and fighting numbers. Accessibility to males was also delayed by neonatal E₂ exposure, although it was shortened by high‐dose EE exposure. In contrast, low‐dose EE‐treated females did not exhibit impaired sexual behaviour. These results suggest that single neonatal exposure to a high dose of EE or E₂ disturbs the normal development of the female brain, resulting in impaired sexual behaviours in a female‐paced mating situation. Besides, the differences noted between high‐dose EE‐ and E₂‐treated females might be caused by different affinities of the oestrogen receptors, metabolic rates or mechanisms of action. Copyright © 2017 John Wiley & Sons, Ltd.     

The pharmacokinetics of amiloride-hydrochlorothiazide combination in the young and elderly

Summary The pharmacokinetics of amiloride and hydrochlorothiazide were studied in 12 healthy young volunteers following a single dose of a fixed combination of amiloride and hydrochlorothiazide and in 11 elderly hypertensive patients at steady-state. Following modelling of the single dose data, simulated steady-state plasma concentrations for the 2 drugs were generated to examine the effect of age and/or hypertension on pharmacokinetics.The apparent systemic plasma clearance for both amiloride and hydrochlorothiazide was significantly reduced in the elderly when compared to the young (from 753 to 325 ml·min^–1, amiloride; and from 418 to 157 ml·min^–1, hydrochlorothiazide). The plasma concentrations at steady state for both drugs were greatly increased in the elderly patients (Amiloride: from 7 to 25 ng·ml^–1, C_ss,max; from 2 to 8 ng·ml^–1, C_ss,min; and from 4 to 14 ng·ml^–1, C_av; Hydrochlorothiazide: from 184 to 651 ng·ml^–1, C_ss,max; from 31 to 121 ng·ml^–1, C_ss,min; and from 89 to 273 ng·ml^–1, C_av).The decreased clearance of the diuretics in the elderly was believed due to deterioration of renal function, and there was a significant correlation between the plasma clearance of hydrochlorothiazide and creatinine clearance in both age groups (r=0.62, young;r=0.72, elderly).As a result of the pharmacokinetic findings caution may be indicated in the clinical dosage of the diuretics particularly when in fixed dose combination.     

Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting

The estradiol(E₂)-loaded chitosan nanoparticles (CS-NPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP). The CS-NPs had a mean size of (269.3 ± 31.6) nm, a zeta potential of +25.4 mV, and loading capacity of E₂ CS-NPs suspension was 1.9 mg ml⁻¹, entrapment efficiency was 64.7% on average. Subsequently, this paper investigated the levels of E₂ in blood and the cerebrospinal fluid (CSF) in rats following intranasal administration of E₂ CS-NPs. E₂-loaded CS-NPs were administered to male Wister rats either intranasally or intravenously at the dose of 0.48 mg kg⁻¹. The plasma levels achieved following intranasal administration (32.7 ± 10.1 ng ml⁻¹; t_max 28 ± 4.5 min) were significantly lower than those after intravenous administration (151.4 ± 28.2 ng ml⁻¹), while CSF concentrations achieved after intranasal administration (76.4 ± 14.0 ng ml⁻¹; t_max 28 ± 17.9 min) were significantly higher than those after intravenous administration (29.5 ± 7.4 ng ml⁻¹ t_max 60 min). The drug targeting index (DTI) of nasal route was 3.2, percent of drug targeting (DTP%) was 68.4%. These results showed that the E₂ must be directly transported from the nasal cavity into the CSF in rats. Finally, compared with E₂ inclusion complex, CS-NPs improved significantly E₂ being transported into central nervous system (CNS).     

Effects of binary mixtures of xenoestrogens on gonadal development and reproduction in zebrafish

Previous studies exposing fish to xenoestrogens have demonstrated vitellogenin (VTG) induction, delayed gametogenesis, altered sex ratio, and decreased reproductive performance, with a majority of those studies focusing on exposure to single chemicals. The objective of this study was to determine the effects of binary mixtures of a weak estrogen receptor agonist, nonylphenol (NP) and a potent estrogen receptor agonist, 17α-ethinylestradiol (EE) on sex ratios, gametogenesis, VTG induction, heat shock protein 70 (HSP70) expression and reproductive capacity in zebrafish (Danio rerio). Fish were exposed from 2 to 60 days post-hatch (dph) to nominal concentrations of 10 or 100 μg/l NP (NP10 or NP100, respectively), 1 or 10 ng/l EE (EE1 or EE10, respectively), 1 ng/l EE + 10 or 100 μg/l NP (EE1 + NP10 or EE1 + NP100, respectively), 10 ng/l EE + 10 or 100 μg/l NP (EE10 + NP10 or EE10 + NP100, respectively) or solvent control (0.01% acetone, v/v) in a static-renewal system with replacement every 48 h. At 60 dph, fish from each treatment were euthanized for histological examination of gonads, and whole body VTG and HSP70 levels. Remaining fish were reared in clean water until adulthood (240 dph) for breeding studies. In all EE10 exposure groups (EE10, EE10 + NP10 and EE10 + NP100), increasing NP concentration acted antagonistically to the action of EE in terms of VTG induction at 60 dph. Similarly, non-additivity was observed with egg production, where EE1 + NP100 exposure resulted in significantly more eggs produced per breeding trial than EE1 alone. Histological staging of oogenesis revealed suppressed gametogenesis in an additive fashion in females at 60 dph. There were no differences among treatment groups in whole body HSP70 expression in 60 dph fish or in gonadal HSP70 expression in adult fish. Although there was no statistical evidence of non-additivity, breeding trials in adults revealed significant reductions in egg viability, egg hatchability and/or F₁ swim-up success, suggesting that developmental exposures to xenoestrogens may cause irreversible effects on egg quality and progeny even after periods of depuration. In conclusion, these results suggest that environmentally relevant mixtures of NP and EE can produce additive or non-additive effects that depend on the particular response being determined and the respective exposure concentrations of each chemical.     

Total and free steady-state plasma levels and pharmacokinetics of nifedipine in patients with terminal renal failure

Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose.The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml^–1) and maximum plasma concentration (75.0 ng·ml^–1) were lower than in subjects with normal renal function (19300 ng·ml^–1; 122 ng·ml^–1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure.Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.     

Pharmacokinetic-pharmacodynamic modelling of the anti-lipolytic and anti-ketotic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine in rats

1. The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A₁-receptor agonist N⁶-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals.
2. After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and β-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously.
3. The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 μg kg⁻¹ in 5 min and 15 min, and 120 μg kg⁻¹ in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean±s.e., n=19) were E_max: −80±2% (% change from baseline), EC₅₀: 22±2 ng ml⁻¹, and Hill factor: 2.2±0.2.
4. In another group, given 400 μg kg⁻¹ SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal E_max model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC₅₀ values (mean±s.e., n=6) were 131±31 ng ml⁻¹ and 20±3 ng ml⁻¹ for heart rate and NEFA lowering effect, respectively.
5. In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

     

Effect of diprafenone on the pharmacokinetics of digoxin

This study was conducted to investigate the effect of diprafenone on the steady-state pharmacokinetics of digoxin. Twelve healthy men, all rapid hydroxylators of debrisoquine, received digoxin (0.5 mg per day over 7 days with a loading dose of 2 × 1 mg) or digoxin and diprafenone (3 × 100 mg per day) in three different phases, without a wash-out period (phase 1, digoxin alone; phase 2, digoxin + diprafenone; phase 3, digoxin alone). Blood and urine samples were collected for pharmacokinetic analyses. Diprafenone caused a statistically significant increase in digoxin trough concentrations [1.4 (SD 0.2) vs 1.6 (0.3) ng ⋅ml⁻¹], AUC_0–24 values [41 (7) vs 48 (9) ng⋅h⋅ml⁻¹ and C_ss-max [3.9 (0.6) vs 5.5 (0.9) ng⋅ml⁻¹]. In all volunteers the parameters tended to return to the original values after administration of diprafenone was discontinued [1.4 (0.3) ng⋅ml⁻¹, 39 (11) ng⋅h⋅ml⁻¹, and 3.9 (1.1) ng⋅ml⁻¹ for trough concentration, AUC_0–24 and C_max respectively]. The mean relative magnitude of the increase in AUC_0–24 and trough concentration values corresponded to the mean relative decrease in the renal clearance of digoxin (in both cases approximately 20%). This suggests that the increase in AUC and C_ss was caused by reduced renal clearance of digoxin. Received: 10 July 1995 /Accepted in revised form: 5 October 1995     

Comparative study of cyto‐ and genotoxic potential with mechanistic insights of tungsten oxide nano‐ and microparticles in lung carcinoma cells

The exigency of semiconductor and super capacitor tungsten oxide nanoparticles (WO₃ NPs) is increasing in various sectors. However, limited information on their toxicity and biological interactions are available. Hence, we explored the underlying mechanisms of toxicity induced by WO₃ NPs and their microparticles (MPs) using different concentrations (0–300 μg ml^–1) in human lung carcinoma (A549) cells. The mean size of WO₃ NPs and MPs by transmission electron microscopy was 53.84 nm and 3.88 μm, respectively. WO₃ NPs induced reduction in cell viability, membrane damage and the degree of induction was size‐ and dose‐dependent. There was a significant increase in the percentage tail DNA and micronuclei formation at 200 and 300 μg ml^–1 after 24 hours of exposure. The DNA damage induced by WO₃ NPs could be attributed to increased oxidative stress and inflammation through reactive oxygen species generation, which correlated with the depletion of reduced glutathione content, catalase and an increase in malondialdehyde levels. Cellular uptake studies unveiled that both the particles were attached/surrounded to the cell membrane according to their size. In addition, NP inhibited the progression of the cell cycle in the G₂/M phase. Other studies such as caspase‐9 and ‐3 and Annexin‐V‐fluorescein isothiocyanate revealed that NPs induced intrinsic apoptotic cell death at 200 and 300 μg ml^–1 concentrations. However, in comparison to NPs, WO₃ MPs did not incite any toxic effects at the tested concentrations. Under these experimental conditions, the no‐observed‐significant‐effect level of WO₃ NPs was determined to be ≤200 μg ml^–1 in A549 cells.     

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients

Summary The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous ¹⁴C-fosinoprilat (7.5 mg), oral ¹⁴C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study.Mean maximum concentration (C_max), clearance (CL), volume of distribution at steady-state (V_ss), mean residence time (MRT_iv), and t_1/2 values after IV administration of ¹⁴C-fosinoprilat were 2,042 g·ml^–1, 11.3 ml·min^–1, 11.01, 16.3 h and 28.3 h, respectively. Following oral administration of ¹⁴C-fosinopril, mean C_max, time to maximum plasma concentration (t_max), and fosinoprilat bioavailability values were 197 ng·ml^–1, 5.2 h and 29.2 %. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15 % and 2 % of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5 % of the administered dose. The maximum effect (E_max) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. E_max ranged from 95.3 to 102.5 %, and IC₅₀ (the fosinoprilat concentration required to produce 50 % of E_max) ranged from 2.6 to 4.2 ng·ml^–1.Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.Presented in part at the Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Antonio, TX, March, 1990     

Assessment of estrogenic contamination and biological effects in Lake Taihu

Lake Taihu is the third largest freshwater lake in China and is contaminated with xenoestrogens associated with high population density, intensive livestock and aquatic breeding activities. A field study in Lake Taihu was conducted using the goldfish (Carassius auratus) as an indicator organism. Several biological markers were selected to assess the extent of estrogenic contamination. Changes in serum vitellogenin (VTG), and gill 7-Ethoxyresorufin-O-deethylase (EROD), glutathione-S-transferase (GST) and reduced glutathione (GSH) were measured in caged juvenile goldfish for 28 days in seven locations in northern Lake Taihu. Bioassay showed VTG increased 0.64–2.42 folds over time in goldfish collected from five stations and GSH decreased in samples from all seven stations after 7 days of exposure. EROD levels increased continually in fish collected at all the seven stations and the highest concentrations occurred at day 21. GST activity increased significantly at 7 days. The concentration of the target estrogens estrone (E₁), 17β-estradiol (E₂), ethinylestradiol (EE₂), octylphenol (OP), diethylstilbestrol (DES), nonylphenol (NP) and bisphenol A (BPA) were determined in lake water at the sampling stations. Each individual estrogen concentration measured was multiplied by its relative potency to gain the estrdiol equivalent (EEQ). There was an obvious correlation between the concentration of VTG and the total EEQ for all seven locations (P < 0.001). The biomarker VTG, EROD, GST and GSH assays and chemical analysis might be used to illustrate the potential risk in Lake Taihu.     

Endocrine disrupting chemicals, 4‐nonylphenol,bisphenol A and butyl benzyl phthalate,impair metabolism of estradiol in male and female rats as assessed by levels of 15α‐hydroxyestrogens and catechol estrogens in urine

Bisphenol A (BPA), 4‐nonylphenol (NP) and butyl benzyl phthalate (BBP), termed endocrine‐disrupting chemicals, are known to mimic estrogen activity. The effects of these chemicals on 17β‐estradiol (E₂) metabolism in vivo in rats were examined. Male and female rats were given NP (250 mg kg^–1 day^–1), BPA (250 μg kg^–1 day^–1) or BBP (500 mg kg^–1 day^–1) by gavage for 14 days, followed by a single intraperitoneal injection of E₂ (5 mg kg^–1) on the final day. The urinary excretion over 72 hours of 2‐hydroxyestrone 1‐N‐acetylcysteine thioether, 2‐hydroxyestrone 4‐N‐acetylcysteine thioether, 4‐hydroxyestrone 2‐N‐acetylcysteine thioether, 2‐hydroxy‐17β‐estradiol (2‐OHE₂), 2‐hydroxyestrone (2‐OHE₁), 4‐hydroxy‐17β‐estradiol, 4‐hydroxyestrone, 15α‐hydroxyestriol (E₄), 15α‐hydroxy‐17β‐estradiol and 15α‐hydroxyestrone was measured. Increases in urinary excretion of 2‐OHE₁ and decreases in E₄ were observed in males treated with NP or BBP. Decreases in urinary excretion of 2‐OHE₂ and E₄ were observed in males treated with BPA. Decreases in urinary excretion of 2‐OHE₁ and 2‐OHE₂ were observed in females treated with BBP. Normalized liver and weights were increased in both sexes treated with NP or BBP. Histologic observations revealed marked changes in the distal tubules and collecting ducts in the kidneys of rats exposed to NP and BBP, and hypertrophy in the hepatocytes of the centrilobular zone of the liver. No BPA‐related effects on organ weight and on liver or kidney histopathology were found. These results suggest that the 14 day oral dosing of NP and BBP disrupted E₂ metabolism, resulting from marked morphological and functional alterations in the liver and kidneys. In addition, BPA could induce metabolic and endocrine disruption.     

Pharmacokinetic interaction between cyclosporin and diltiazem

Summary Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng·ml^–1 to 170 ng·ml^–1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng·ml^–1 before to 336 ng·ml^–1.Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitve inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.     

Pharmacokinetics of cyclosporine in hyperlipidaemic long-term survivors of heart transplantation

Summary Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng·ml^–1), C_max (812 ng·ml^–1 by RIA and 757 ng·ml^–1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); t_max (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t_1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h).The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.Michel de Lorgeril is a fellow from la Fondation pour la Recherche Médicale