1 Paracetamol hepatotoxicity has been found to be potentiated by anticonvulsant drugs in animal experiments; isolated case reports in humans sugest that long-term anticonvulsant therapy may also adversely influence outcome following overdose. 2 We compared the clinical course, after paracetamol overdose, of 18 patients on long-term anticonvulsant therapy with corresponding features in two published series of paracetamol-induced fulminant hepatic failure from this unit: 297 patients seen between 1973 and 1985 and a further 99 between October 1986 and April 1988. 3 Mortality in those patients who were taking anticonvulsants, but who did not receive N-acetylcysteine, was higher than in either of these series (93.3% vs 64.6% and vs 57.9%, P< 0.025). Although not statistically significant, there were also trends towards more severe coma (grade 3 or 4: 93.3% vs 75.4%, 1986-88), acidosis (pH less than 7.30: 40% vs 22.6%, 1973-85) and coagulopathy (prothrombin time greater than 100 s: 53.3% vs 33.7%, 1973-85). In the small number of patients given N-acetylcysteine, mortality was similar to that in the 1986-88 series (1/3 vs 15/42). 4 We conclude that chronic use of anticonvulsants enhances clinical features of paracetamol toxicity and discuss possible mechanisms by which this could be mediated.

Additional key phrases: immunosuppressant drugs; analytical methods; transplantationDuring the last decade a growing number of centres have become involved in the measurement of the immunosuppressive agent cyclosporin, When the UK Cyclosporin Quality Assessment Scheme (UKCQAS) was started by two of us (DH and AI) in 1984 there were 14 participants in the UK; now there are over 50. The increasing number of indications for which cyclosporin can be prescribed, together with the proliferation of centres capable of performing organ transplantation, suggests that an even larger number of laboratories are likely to offer this assay as a service in the future. The purpose of this review is to summarize current information relating to cyclosporin monitoring and to give some indication of the clinical problems surrounding the use of the results. It has been written against the background of three consensus documents, based on input from laboratory scientists and clinicians, all of which have arrived at similar concluslons.l ? Since these consensus reports were written there have been some changes with regard to the immunoassays available for cyclosporin measurement and there have been a number of reports documenting the performance of the newest assays.The present authors have all been involved in the measurement of cyclosporin in a variety of clinical settings and intend that this review should allow laboratory workers and clinicians to make an informed choice when deciding which method to use for the measurement of cyclosporin. To this end we have drawn upon recent literature, Correspondence: Dr D W Holt. 420 our own experience in this field, data from the UKCQAS, and we have surveyed current practices in UK laboratories performing the measurement.We have chosen to concentrate on three main areas. First, the pharmacology of the drug, since this is essential to an appreciation of the methodological problems associated with cyclosporin measurement. Secondly, we have produced a detailed review of analytical methods and their relative performance. Thirdly, we present a summary of the clinical factors which influence the interpretation of the results in the diverse clinical settings in which cyclosporin is used, to provide those who are producing the cyclosporin results with some insight into the problems faced by those who have to use the data. CYCLOSPORINSince the cyclic peptide cyclosporin (cyclosporin A, ciclosporin, cyclosporine, Sandimmun@) began to be included in immunosuppressive protocols, it has had a profound effect on clinical transplantation world-wide, not only in terms of improved organ and patient survival but also in improving more positive public attitudes towards transplantation. One major disappointment which emerged with the clinical use of cyclosporin was that therapeutic doses in man caused a number of adverse side-effects, in contrast to many of the animal species studied. These sideeffects included renal and hepatic dysfunction, hypertension, neurotoxicity, lymphoma, abnormal glucose homeostasis, hyp...

1. Cyclosporin A absorption was examined after the instillation of approximately 2 mg/kg into four segments (mean length 15 cm) of rat small bowel, isolated in situ in fed Wistar female rats: SI (duodenum and proximal jejunum distal to the common bile duct); SII (distal jejunum); SIII (proximal ileum) and SIV (distal ileum). 2. Cyclosporin A concentrations in whole blood were assayed by an enzyme-mediated immunoassay for up to 4 h in samples drawn from the femoral vein and used to determine the following pharmacokinetic parameters: the area under the blood cyclosporin A concentration versus time curve (AUC, 0-4 h), the maximum blood concentration of cyclosporin A (Cmax.), the time to reach Cmax. (tmax.), the absorption half-life (t1/2a), the elimination half-life (t1/2 lambda), and the mean residence time (MRT). 3. Cyclosporin A absorption in SI (AUC, 991 micrograms l-1 h) was nearly double that in more distal segments and decreased progressively (SII, 533 micrograms l-1 h; SIII, 470 micrograms l-1 h; SIV, 419 micrograms l-1 h). There were corresponding differences in Cmax.: 327 micrograms/l in SI and 201 micrograms/l, 169 micrograms/l and 151 micrograms/l in SII, SIII and SIV, respectively. Tmax. was shorter in SIV (0.9 h) than in other segments (1.3-1.5 h), but there were no significant differences between the segments for t1/2a, t1/2 lambda or MRT. 4. In the presence of continuous bile flow (diverted via a cannula for SIV), cyclosporin A absorption significantly increased by 23% in SI and by 50% in SIV, but the differential between absorption in SI and SIV was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)

After administration to mice of a hepatotoxic dose of paracetamol (400 mg/kg body wt, p.o.) peak plasma concentrations of the drug and its glucuronide were approximately 900 microM around one hour. Corresponding levels of the sulphate, mercapturate and cysteine conjugates were approximately 100, 35 and 20 microM, respectively. Urinary excretion accounted for 55% of the administered drug 31 h after dosing. Of this total, 64.7% was paracetamol glucuronide, 17.9% paracetamol cysteine, 10.4% paracetamol sulphate, 0.5% paracetamol mercapturate and 6.5% unchanged drug. One hour after acute ethanol administration (3 g/kg, p.o., concomitantly with paracetamol) plasma levels of the glucuronide, cysteine and mercapturate conjugates were decreased by approximately 50%. There were reductions in the urinary excretion of the glucuronide (-13%) and cysteine conjugates (-24%), but increases in the amounts of mercapturate (+52%), sulphate +11%) and unchanged drug (+81%). Chronic ethanol ingestion (15 g/kg per d for 28 d) caused a transient initial increase in plasma paracetamol cysteine (+32%) and mercapturate (+41%) concentrations, but the only substantial change in urinary excretion was a 29% increase in the amount of paracetamol glucuronide. After chronic ethanol consumption, acute ethanol administration had a transient inhibitory effect on paracetamol mono-oxygenation, but glucuronidation was unaffected (as judged by plasma concentrations). Only paracetamol mercapturate excretion was substantially affected (+64%).