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Aims The aims of the study were to compare [14C]‐paracetamol ([14C]‐PARA) paediatric pharmacokinetics (PK) after administration mixed in a therapeutic dose or an isolated microdose and to develop further and validate accelerator mass spectrometry (AMS) bioanalysis in the 0–2 year old age group. Methods [14C]‐PARA concentrations in 10–15 µl plasma samples were measured after enteral or i.v. administration of a single [14C]‐PARA microdose or mixed in with therapeutic dose in infants receiving PARA as part of their therapeutic regimen. Results Thirty‐four infants were included in the PARA PK analysis for this study: oral microdose (n = 4), i.v. microdose (n = 6), oral therapeutic (n = 6) and i.v. therapeutic (n = 18). The respective mean clearance (CL) values (SDs in parentheses) for these dosed groups were 1.46 (1.00) l h–1, 1.76 (1.07) l h–1, 2.93 (2.08) l h–1 and 2.72 (3.10) l h–1, t1/2 values 2.65 h, 2.55 h, 8.36 h and 7.16 h and dose normalized AUC(0‐t) (mg l–1 h) values were 0.90 (0.43), 0.84 (0.57), 0.7 (0.79) and 0.54 (0.26). Conclusions All necessary ethical, scientific, clinical and regulatory procedures were put in place to conduct PK studies using enteral and systemic microdosing in two European centres. The pharmacokinetics of a therapeutic dose (mg kg–1) and a microdose (ng kg–1) in babies between 35 to 127 weeks post‐menstrual age. [14C]‐PARA pharmacokinetic parameters were within a two‐fold range after a therapeutic dose or a microdose. Exploratory studies using doses significantly less than therapeutic doses may offer ethical and safety advantages with increased bionalytical sensitivity in selected exploratory paediatric pharmacokinetic studies.

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The mutagenicity of 1-nitropyrene and its reduced metabolite 1-nitrosopyrene was determined in the lambda cI gene of an Escherichia coli uvr- lysogen. 1-Nitropyrene induced a mutation frequency of 3.8 x 10(-6), which was approximately 2-fold higher than the background mutation frequency, whereas an equimolar dose of 1-nitrosopyrene induced a much higher mutation frequency of 1.4 x 10(-4). Previous studies have established that both compounds form the same premutagenic lesion, viz. N-(deoxyguanosin-8-yl)-1-aminopyrene in bacterial DNA. In order to determine how this initial premutational lesion is converted to a stable heritable mutation, DNA sequences were determined for 30 mutations induced by 1-nitrosopyrene that mapped between bp 1 and 352 in the lambda cI gene of E.coli lysogens. We show here that these mutations are mainly frameshifts involving the addition or deletion of a single GC or CG base pair. A small proportion of mutations were base substitutions which were equally divided between transitions and transversions. These also occurred primarily at GC or CG sites.

Purpose:To investigate the potential use of accelerator mass spectrometry (AMS) in the study of the clinical pharmacology of imatinib. Experimental Design: Six patients who were receiving imatinib (400 mg/d) as part of their ongoing treatment for chronic myeloid leukemia (CML) received a dose containing a trace quantity (13.6 kBq) of 14 C-imatinib. Blood samples were collected from patients before and at various times up to 72 h after administration of the test dose and were processed to provide samples of plasma and peripheral blood lymphocytes (PBL). Samples were analyzed by AMS, with chromatographic separation of parent compound from metabolites. In addition, plasma samples were analyzed by liquid chromatography/mass spectrometry (LCMS). Results: Analysis of the AMS data indicated that imatinib was rapidly absorbed and could be detected in plasma up to 72 h after administration. Imatinib was also detectable in PBL at 24 h after administration of the 14 C-labeled dose. Comparison of plasma concentrations determined by AMS with those derived by LCMS analysis gave similar average estimates of area under plasma concentration time curve (26 F 3 versus 27 F 11 Ag/mLÁh), but with some variation within each individual. Conclusions: Using this technique, data were obtained in a small number of patients on the pharmacokinetics of a single dose of imatinib in the context of chronic dosing, which could shed light on possible pharmacologic causes of resistance to imatinib in CML.

A workshop was held to critically discuss the need for a non-rodent species and the role of the dog in regulatory toxicity testing of pharmaceuticals; to discuss opportunities to reduce and refine the use of dogs in preclinical toxicology; and to identify a number of specific recommendations which could be feasibly achieved to move the process forward. To facilitate a preliminary evaluation of the contribution of dog studies to the risk assessment process, anonymised, unpublished data were provided from fully evaluated, repeat dose toxicity studies in the rat and dog. Results ofthe International Life Sciences Institute (ILSI) Human Toxicity Project were also presented and discussed. Analysis of the data demonstrated that the dog can provide additional toxicity information, which, in some cases, was shown to be predictive for humans. Discussions indicated that there is potential for achieving a reduction in dog use and several possible approaches were identified. To further the progress of this initiative, there is a need to collate the results of pharmacology, toxicology, and clinical studies to address some of the proposed approaches. One of the outcomes of the workshop will be the establishment of a steering group to co-ordinate data collation for further analysis.

BACKGROUND AND PURPOSEProlongation of the cardiac QRS complex is linked to increased mortality and may result from drug-induced inhibition of cardiac sodium channels (hNaV1.5). There has been no systematic evaluation of preclinical and marketed drugs for their additional potential to cause QRS prolongation via gap junction uncoupling. EXPERIMENTAL APPROACHUsing the human cardiac gap junction connexin 43 (hCx43), a dye transfer 'parachute' assay to determine IC50 values for compound ranking was validated with compounds known to uncouple gap junctions. Uncoupling activity (and hNaV1.5 inhibition by automated patch clamp) was determined in a set of marketed drugs and preclinical candidate drugs, each with information regarding propensity to prolong QRS. KEY RESULTSThe potency of known gap junction uncouplers to uncouple hCx43 was ranked (according to IC50) as phorbol ester>digoxin>meclofenamic acid>carbenoxolone>heptanol. Among the drugs associated with QRS prolongation, 29% were found to uncouple hCx43 (IC50 < 50 μM), whereas no uncoupling activity was observed in drugs not associated with QRS prolongation. In preclinical candidate drugs, hCx43 and hNaV1.5 IC50 values were similar (within threefold). No consistent margin over preclinical Cmax (free) was apparent for QRS prolongation associated with Cx43 inhibition. However, instances were found of QRS prolonging compounds that uncoupled hCx43 with significantly less activity at hNaV1.5. CONCLUSION AND IMPLICATIONSThese results demonstrate that off-target uncoupling activity is apparent in drug and drug-like molecules. Although the full ramifications of Cx inhibition remain to be established, screening for hCx43 off-target activity could reduce the likelihood of developing candidate drugs with a risk of causing QRS prolongation. AbbreviationsCx, connexin; PDBu, phorbol 12,13-dibutyrate