High amounts of acrylamide in some foods result in an estimated daily mean intake of 50 microg for a western style diet. Animal studies have shown the carcinogenicity of acrylamide upon oral ...exposure. However, only sparse human toxicokinetic data is available for acrylamide, which is needed for the extrapolation of human cancer risk from animal data. We evaluated the toxicokinetics of acrylamide in six young healthy volunteers after the consumption of a meal containing 0.94 mg of acrylamide. Urine was collected up to 72 hours thereafter. Unchanged acrylamide, its mercapturic acid metabolite N-acetyl-S-(2-carbamoylethyl)cysteine (AAMA), its epoxy derivative glycidamide, and the respective metabolite of glycidamide, N-acetyl-S-(2-hydroxy-2-carbamoylethyl)cysteine (GAMA), were quantified in the urine by liquid chromatography-mass spectrometry. Toxicokinetic variables were obtained by noncompartmental methods. Overall, 60.3 +/- 11.2% of the dose was recovered in the urine. Although no glycidamide was found, unchanged acrylamide, AAMA, and GAMA accounted for urinary excretion of (mean +/- SD) 4.4 +/- 1.5%, 50.0 +/- 9.4%, and 5.9 +/- 1.2% of the dose, respectively. Apparent terminal elimination half-lives for the substances were 2.4 +/- 0.4, 17.4 +/- 3.9, and 25.1 +/- 6.4 hours. The ratio of GAMA/AAMA amounts excreted was 0.12 +/- 0.02. In conclusion, most of the acrylamide ingested with food is absorbed in humans. Conjugation with glutathione exceeds the formation of the reactive metabolite glycidamide. The data suggests an at least 2-fold and 4-fold lower relative internal exposure for glycidamide from dietary acrylamide in humans compared with rats or mice, respectively. This should be considered for quantitative cancer risk assessment.
Background And Objectives
Because of extensive first‐pass metabolism, oral bioavailability of sildenafil reaches only 40%. Formation of the primary metabolite, N‐desmethylsildenafil, is mainly ...mediated by the cytochrome P450 enzyme CYP3A4. In this study we investigated the influence of grapefruit juice, containing inhibitors of intestinal CYP3A4, on the pharmacokinetics of sildenafil and N‐desmethylsildenafil.
Methods
In a randomized crossover study, 24 healthy white male volunteers received single 50‐mg doses of sildenafil. Two doses each of 250 ml grapefruit juice or water, respectively, were administered 1 hour before and together with the drug. Plasma concentrations of sildenafil and N‐desmethylsildenafil were determined up to 24 hours post dose by use of liquid chromatography–tandem mass spectrometry (limit of quantification, 1 ng/ml).
Results
Grapefruit juice changed the area under the sildenafil plasma concentration–time curve from time zero to infinity AUC(0‐∞) from 620 1.53 ng/ml • h to 761 1.58 ng/ml • h (geometric mean with geometric standard deviation), corresponding to a 23% increase (90% confidence interval, 13%‐33%). N‐Desmethylsildenafil AUC(0‐∞) increased by 24% (90% confidence interval, 17%‐32%). Maximum plasma concentrations (Cmax) of sildenafil and N‐desmethylsildenafil were essentially unchanged. There was a trend toward a prolonged time to reach Cmax during the grapefruit juice period (from a median of 0.75 hour to a median of 1.13 hours), corresponding to an increase by 0.25 hour (90% confidence interval, 0–0.63 hour). Interindividual variability was pronounced in both periods.
Conclusions
Grapefruit juice increases sildenafil bioavailability and tends to delay sildenafil absorption. Sildenafil pharmacokinetics may become less predictable with grapefruit juice. Although patients usually will not be endangered by concomitant use of grapefruit juice, it seems advisable to avoid this combination.
Clinical Pharmacology & Therapeutics (2002) 71, 21–29; doi: 10.1067/mcp.2002.121236
Abstract Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability ...of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• Most β‐lactams are excreted by filtration and to a greater extent by tubular secretion, which is a capacity‐limited saturable pathway.
• Pharmacokinetic ...interactions between co‐administered β‐lactams have been frequently reported; however, their mechanism and possible clinical benefits are not well defined.
• We are not aware of the interaction between piperacillin and flucloxacillin being reported in the literature.
WHAT THIS STUDY ADDS
• Piperacillin inhibits the renal and nonrenal elimination of flucloxacillin to a clinically significant extent, but not vice versa.
• Modelling suggests that the mechanism for the decrease of renal clearance of flucloxacillin is probably competitive inhibition of renal tubular secretion by piperacillin.
• Piperacillin has a 15‐times higher affinity for the renal transporter than flucloxacillin based on the molar ratio.
AIMS
To explore the extent, time course, site(s), mechanism and possible clinical relevance of the pharmacokinetic (PK) interaction between piperacillin and flucloxacillin.
METHODS
A single‐dose, randomized, six‐way crossover study in 10 healthy volunteers where all subjects received all of the following as 5‐min intravenous infusions: (i) 1.5 g piperacillin, (ii) 0.5 g flucloxacillin, (iii) 1.5 g piperacillin + 0.5 g flucloxacillin, (iv) 3 g piperacillin, (v) 1 g flucloxacillin, and (vi) 3 g piperacillin + 1 g flucloxacillin. Drug concentrations in plasma and urine were determined by high‐performance liquid chromatography. WinNonlin® was used for PK modelling and statistics.
RESULTS
Piperacillin significantly decreased the renal clearance of flucloxacillin from 5.44 to 2.29 l h−1 (medians, P < 0.01) and the nonrenal clearance of flucloxacillin from 2.67 to 1.80 l h−1 (P < 0.01). The renal clearance of flucloxacillin was reduced to 45% (point estimate, 90% confidence interval 40 to 50%) and the nonrenal clearance to 66% (59, 73). The extent of interaction was larger at the higher doses. Competitive inhibition of tubular secretion by piperacillin was identified as the most likely mechanism for the decreased renal clearance of flucloxacillin. Piperacillin had a 15‐times higher affinity for the renal transporter than flucloxacillin based on the molar ratio. Piperacillin PK was only slightly affected by flucloxacillin.
CONCLUSIONS
Piperacillin inhibits renal and nonrenal elimination of flucloxacillin. This interaction seems clinically significant, as total clearance was reduced by a factor of 1.5 for the lower and 2.1 for the higher doses. PK interactions, especially with piperacillin, are likely to occur also with other β‐lactam combinations and might be useful to improve the effectiveness of antibacterial treatment.
Technical advances in the field of quality analysis allow an increasingly deeper look into the impurity profile of drugs. The ability to detect unexpected impurities in addition to known impurities ...ensures the supply of high-quality drugs and can prevent recalls due to the detection of harmful unexpected impurities, as has happened recently with the N-nitrosamine and azido impurities in losartan (LOS) drug products. In the present study, the LC-MS/HRMS approach described by Backer et al. was applied to an even more complex system, being the investigation of 35 LOS drug products and combination preparations purchased in 2018 and 2022 in German pharmacies. The film-coated tablets were analysed by means of four LC-MS/HRMS method variants. For the separation a Zorbax RR StableBond C18 column (3.0 ×100 mm, particle size of 3.5 µm, pore size of 80 Å), a gradient elution and for mass spectrometric detection a qTOF mass spectrometer with electrospray ionization in positive and negative mode was used. An information-dependent acquisition method was applied for the acquisition of high-resolution mass spectrometry data. The combination of an untargeted and a targeted screening approach revealed the finding of eight impurities in total. Beside the five LOS related compounds, LOS impurity F, J, K, L, M, and related compound D from amlodipine besilate, LOS azide and an unknown derivative thereof were detected. Identification and structure elucidation, respectively, were successfully performed using in silico fragmentation. Differences in the impurity profiles of drug products from 2018 and 2022 could be observed. This study shows that broad screening approaches like this are applicable to the analysis of drug products and can be an important enhancement of the quality assurance of medicinal products.
Display omitted
•Analysis of losartan finished dosage forms by means of HRMS.•Structural elucidation by means of MS and MS/MS data.•Verification of proposed structural formulae by in silico fragmentation.•Comparison of the impurity profiles of losartan tablets purchased in 2018 and 2022.•Development of a procedure which provides a broad look into the impurity profile of drugs.
•Rifampicin drugs are contaminated with 4-methyl-1-nitrosopiperazine up to 5.1 ppm.•Intake of contaminated rifampicin justifiable in its use against severe diseases.•Rifampicin synthesis shows a high ...risk for 4-methyl-1-nitrosopiperazine formation.•Advanced impurity profiling strategies might avoid future nitrosamine occurrences.
Upon emergence of nitrosamines in various drugs, e.g in valsartan, metformin and ranitidine, 4-methyl-1-nitrosopiperazine (MeNP) was found in rifampicin in August 2020. Rifampicin is used, amongst others, for post-exposure prophylaxis of leprosy. The occurrence of MeNP can be explained by the synthesis, because 1-amino-4-methylpiperazine is concomitantly used with the organic oxidizing reagent isoamyl nitrite. According to a method reported by the FDA, the quantification of MeNP in rifampicin capsules was performed by LC–MS/HRMS. A significant contamination with MeNP was found in all samples, ranging from 0.7 to 5.1 ppm and exceeding the acceptable intake limit proposed by the FDA up to 32-fold. However, the severity of a possible leprosy infection outweighs the risks, which are concomitant with the intake of a single dose of rifampicin for post-exposure prophylaxis. Nevertheless, the extent of contamination is alarming, and countermeasures are needed to minimize public health risks. The presence of nitrosamines in rifampicin illustrates the need for better strategies in impurity profiling and compendial testing once again.
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