PubMed · 11799572
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J Joris, A Kaba. 2001. Interactions between systemic analgesics.. https://pubmed.ncbi.nlm.nih.gov/11799572/
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Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl(4)) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1). Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl(4) p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6beta-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and alpha-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration. Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A.
A method for the determination of 4-aminophenol as an impurity in paracetamol (N-(4-hydroxyphenyl)-acetamide) by proton nuclear magnetic resonance ((1)H-NMR) spectroscopy has been developed. The (13)C-satellite from the protons in the ortho position from the hydroxyl group in paracetamol was used as an internal standard, although these peaks interfered with the peaks from the protons in 4-aminophenol. Because of interference in the spectra and non-linearity over a wide calibration range, a Bayesian regularized neural network model was used for calibration. Various kinds of data preprocessing were examined: zero filling, multiplication by a negative exponential function (line broadening), followed by Fourier transformation of the free induction decay (FID). The NMR spectral data were automatically phased and shift-adjusted by means of a genetic algorithm. Multiplicative scatter correction and data compression by wavelets and sequential zeroing of weights variable selection were performed to obtain an optimal calibration model. Neither zero filling of the FID nor line broadening improved the calibration models with regard to error of prediction, so these processes were excluded in the final model. The generated Bayesian regularized network model was evaluated with an independent test set. Four different models with different test sets were constructed to explore the quality of the calibration. The mean error of the optimal calibration model was 25.3 x 10(-6) weight of 4-aminophenol per weight paracetamol. The method is characterized by being relative fast, simple and sufficient sensitive for typical pharmaceutical impurity determinations.
FT-IR and Raman spectroscopic methods are suggested for identification of orthorhombic (form II) and monoclinic (form I) paracetamol and for their quantitative determination in mixes. The intensity ratio of the 836 cm(-1) FT-IR band (attributed to the presence of both forms) to the 806 cm(-1) monoclinic band plotted against the inverse monoclinic molar fraction (X) yields a straight line: I(836)/I(806)=0.515/X+0.700, r=0.9965 for eight calibration points on the regression line. Similarly, the area under the 454 cm(-1) band in FT-Raman spectra (which is attributed to both forms) over the area under the 465 cm(-1) band of monoclinic form is inversely related to its molar fraction (X): A(454)/A(465)=0.482/X-0.324, r=0.9954 for eight calibration points. Precision (RSD%) was <5% for both methods. Linear regression analysis between content and intensity of characteristic XRD reflections for four different samples gave r=0.9964 at 4.62 A and r=0.9894 at 3.70 A, for form II. For the content of form I, r=0.9596 at 3.37 A. The limit of detection for monoclinic form was estimated to be 0.012 mole fraction for both methods.