Spontaneous reporting of adverse drug reactions in an Italian region: Six years of analysis and observations

Pharmacovigilance started in Italy in 1965, and from 1987 reporting of ADRs has been mandatory. Doctors have to send the filled forms on suspected ADRs to the Local Health Districts which transmit biannually all the reports to the Health Department. In a Northern Italian Region (Veneto) spontaneous reporting of adverse drug reactions (ADRs) has been studied during the period 1988–1993. This Region contributes a substantial percentage of the total Italian reports. The total number of reports was 3700, most of these (54 per cent) coming from GPs. A great variability in the reporting rate among the 36 districts of Veneto Region (range: 0–8.8 per 10,000 inhabitants per year) and an important under-reporting have been evident. Underreporting is also emphasized by the fact that in 1993 the Veneto doctors who sent at least one report were only 2.7 per cent. On the whole about 35 per cent of reports concerned minor reactions caused by drugs which have a well known toxicological profile. Comparison between reports coming from Veneto and the UK in some cases show a similar safety profile (omeprazole and simvastatin), whereas in other cases (e.g. terfenadine, glafenine, fluoxetine) no correspondence can be found. This article reveals the limits of the actual spontaneous reporting in Italy and suggests some possible measures for improving it.     

血浆置换治疗吉兰-巴雷综合征临床及护理分析

目的 观察血浆置换治疗吉兰-巴雷综合征(GBS)的疗效,总结护理干预措施对患者生活自理能力的影响.方法 选取GBS住院患者40例,其中男21例,女19例,对其进行基础治疗及血浆置换治疗,2～3h/次,一般为一疗程1～5次,每次置换血浆量为2～3L,治疗前及治疗过程中均给予护理干预措施.观察其临床效果并采用日常生活活动能力量表(ADL)进行生活自理能力的评定.结果 40例GBS患者经血浆置换治疗后,肌力减退改善者总有效率为97.5％ (39/40);感觉减退改善者总有效率为95.7％ (22/23);呼吸困难改善者总有效率为94.1％(16/17);伴吞咽障碍改善者总有效率为90.0％ (9/10);肌肉酸痛者显效5例,好转1例,总有效6例,占75.0％;6例胸闷、气短及心前区不适者均显效(100.0％);周围性面瘫者有效1例,占25.0％.血浆置换前后ADL评分分别为(34±14)、(71 ±23)分,治疗后明显高于治疗前,差异有统计学意义(t=2.448,P=0.016).血浆置换治疗后不良反应发生率为10.4％ (16/154).结论 血浆置换是治疗GBS较为有效的方法.通过对患者进行血浆置换前、中、后的护理及不良反应的预防和护理,可以减少不良反应发生率,提高GBS患者的生活自理能力.     

Treatment of Guillain-Barré syndrome: a review

Guillain-Barré syndrome is a frequently post-infectious, autoimmune acute inflammatory polyradiculoneuropathy affecting all age groups. It typically results in rapid-onset weakness symmetrically affecting proximal and distal muscles. Cranial muscles are not infrequently affected and respiratory muscle weakness requiring mechanical ventilation occurs in 25% of cases. The incidence is around 1-2 per 100,000/year. Various clinical, electrophysiological and immunological subtypes are described. Plasma exchanges (PE) and intravenous immunoglobulins (IVIg) represent the main treatment options. PE were shown to be effective on rate of recovery in randomized trials. Subsequently further trials have demonstrated the equivalence of IVIg. IVIg are frequently the preferred option for practical reasons. Treatment can result in reversible clinical fluctuations which need to be readily recognized. Although number of PE appears to be optimally of 4, except in mildly affected patients where only 2 may suffice, the dosage of IVIg conventionally administered (2 g/kg) may be sub-optimal in some patients. This may relate to a relationship between IVIg pharmacokinetics and clinical outcome. Studies are under way to evaluate the usefulness of a second IVIg course in severely-affected GBS patients. There is no evidence for use of corticosteroids in GBS. Both IVIg and PE are costly and despite their use and established effectiveness, there is still a need for new treatments to lessen disability. Further research is warranted in optimizing currently available therapies as well as finding others to effectively improve the management of this potentially devastating condition.     

血浆置换联合鞘内注射激素治疗重症神经系统脱髓鞘疾病

目的评价血浆置换联合鞘内注射激素治疗重症神经系统脱髓鞘疾病。方法回顾性分析血浆置换联合鞘内注射激素治疗重症格林-巴利综合征11例和重症多发性硬化9例的临床症状转归及治疗前后血中免疫球蛋白滴度变化。结果患者球麻痹、呼吸肌麻痹、四肢肌力在治疗后明显缓解,这二类患者的临床缓解率分别为72.7%和77.8%;治疗后血中免疫球蛋白滴度明显减少(P<0.05)。结论血浆置换联合鞘内注射激素临床疗效肯定,不良反应少,可作为治疗重症格林-巴利综合征及重症多发性硬化的首选方法。     

Diclofenac, paracetamol, and vidarabine removal during plasma exchange in polyarteritis nodosa patients.

Since plasma exchange (PE) represents a major treatment for patients suffering from systemic diseases, its influence on the kinetics of three drugs was investigated: vidarabine, used in patients with polyarteritis nodosa associated with hepatitis B virus (eight subjects), and diclofenac and paracetamol for investigative purposes (five subjects). This study confirmed that vidarabine is so rapidly deaminated to form hypoxanthine arabinoside (Hx-Ara) that no detectable concentrations were measured. Hx-Ara levels were used to evaluate vidarabine kinetics; 19.5 +/- 14.6 mg of Hx-Ara were removed by one PE during the first week of treatment (15 mg kg-1 d-1, continuous infusion) and 7.8 +/- 10.2 mg were eliminated by one PE during the second week of treatment (7.5 mg kg-1 d-1, continuous infusion). Based on the vidarabine intake per hour and the resulting quantity of Hx-Ara removed per hour, PE recovery was quite important (ca. 30 per cent), during both the first and second weeks of continuous infusion. Data were subject to large interindividual variability. However, these results do not favor vidarabine dosage supplementation in this indication because the duration of PE is less than 8 per cent of a daily administration period. For paracetamol (1 g, single oral dose) and diclofenac (100 mg, single oral dose), the fractions of drug removed during PE effected within 2 h of drug intake, were respectively 5.0 +/- 3.1 per cent and 13.6 +/- 9.5 per cent, while plasmapheretic clearance reached, respectively, 13.0 +/- 10.7 per cent of the systemic clearance for paracetamol and 23.0 +/- 1.0 per cent for diclofenac.     

Low tolerability of carbamazepine in psychiatric patients may restrict its clinical usefulness

There are reports of prophylactic efficacy of carbamazepine (CBZ) in manic depres sives when compared with placebo and chlorpromazine. Following a successful open pilot study by one of the authors, an attempt was made to compare carbamazepine and lithium carbonate in a double-blind, crossover trial, each patient being assigned to take each drug for 9 months in random order. However, of the first 14 patients to take carbamazepine four were withdrawn because of drug rashes and another two because of other adverse effects. The trial was discontinued, and a casenotes survey of 50 consecutive psychiatric patients who had been prescribed carbamazepine for mood disorders was then carried out, to establish the tolerability of the drug in clinical practice. Of these, 22 per cent had suffered dizziness, nausea or unsteadiness despite slow introduction of doses. Drug rashes occurred in 16 per cent of patients within the two weeks of starting treatment. A further 14 per cent had other unwanted effects. In total, 36 per cent of the patients had the drug stopped because of adverse effects. With regard to efficacy, in those taking the drug for more than 4 weeks, clinicians reported a definite or probable advantageous effect in 62 per cent of the sample, definite or probable lack of effect in 19 per cent and no opinion in 19 per cent. This low tolerability is not in accordance with previous reports of 2-6 per cent incidence of drug rashes and 10 per cent overall intolerance in neurological patients. We conclude that tolerability is a major drawback to the use of carbamazepine in some groups of psychiatric patients, although all the side- effects were reversible. However, clinical impressions suggested that in a number of patients no other therapeutic strategy was as effective in preventing mood swings.     

Drug-related problems as a cause of hospital admissions in Hong Kong

The importance of drug-related problems as a cause of hospital admissions in Hong Kong was studied in 925 patients admitted to two general medical wards at the Prince of Wales Hospital between November 1992 and February 1993. Drug-related problems were judged to be the main reason for hospital admissions in 88 patients (9.5 per cent). These were adverse drug reactions (n = 57), drug poisoning (n = 22) and treatment failure consequent to noncompliance or inappropriate reduction in dosage (n = 9). The most important adverse drug reactions were gastrointestinal hemorrhage (36.8 per cent) and hypoglycemia (24.6 per cent), and the three drug classes that were most commonly involved were non-steroidal anti-inflammatory drugs (NSAIDs) (aspirin 12.3 per cent, non-aspirin 28.1 per cent), sulphonylureas (19.3 per cent) and diuretics (12.3 per cent). Drug-related problems are an important cause of hospital admissions, and much of the drug-induced illnesses in Hong Kong could be preventable if particular attention was given to NSAID and sulphonylurea therapy. Patients should also be educated about the importance of good drug compliance.     

双重滤过血浆置换治疗吉兰-巴雷综合征与视神经脊髓炎的疗效观察

目的 观察比较全血浆置换(PE)与双重滤过血浆置换(DFPP)对吉兰-巴雷综合征(GBS)与视神经脊髓炎(NMO)的治疗效果及不良反应情况.方法 选取解放军第174医院2014年5月至2016年12月17例神经系统免疫性疾病患者,其中GBS 10例,NMO 7例,所有患者均符合诊断标准.17例患者随机分为2组,PE组8例(GBS 5例,NMO 3例),DFPP组9例(GBS 5例,NMO 4例),2组患者在性别、年龄及疾病严重程度评分上差异无统计学意义(P＞0.05).PE组行全血浆置换25例次,DFPP组行双重滤过血浆置换27例次,2组均采取隔日一次血浆置换的方法,观察2组患者进行血浆置换治疗后肌力、视力恢复情况,皮肤瘙痒、低血压等不良反应发生情况,血浆免疫球蛋白、补体和纤维蛋白原变化情况.结果 2组患者的肌力、视力均获得改善.PE组总体有效率75％,DFPP组总体有效率88％,2组有效率比较差异无统计学意义(P＞0.05).DFPP组患者治疗后补体、免疫球蛋白及纤维蛋白原较治疗前均明显下降(P＜0.05).PE组有3例出现输血反应,DFPP组有1例并发感染,1例并发出血.结论 PE及DFPP均能有效地治疗神经系统免疫性疾病,临床上如血源供应紧张或患者对异体血浆不能耐受,可选择行双重血浆置换治疗,但需注意预防出血及感染等不良反应.     

Ocular absorption and disposition of phenylephrine and phenylephrine oxazolidine

The ocular bioavailability of phenylephrine oxazolidine (PO), a prodrug intended for rapid corneal penetration, was micronized and suspended in sesame oil (1 and 10 per cent) and compared in bioavailability to phenylephrine HC1 (PE) dissolved (10 per cent) in a buffered (pH 5.75), viscous (30 centipoise) vehicle. Cornea and aqueous humor of New Zealand rabbits were measured over time following 10 microliter instillation to the eye. Based upon AUC measurements, corneal and aqueous humor levels were approximately 6 and 8 times greater for 10 per cent PO versus 10 per cent PE, respectively. In addition, the ocular pharmacokinetic values were determined for PE applied in a constant concentration (1 per cent) to the cornea over 180 min to anesthetized rabbits. Cornea and aqueous humor were measured for drug content over time. Using moment analysis and an initial slope method, the absorption rate constant, ka, the steady state volume of distribution in the eye, Vss, and ocular clearance, Qe, were calculated. Values obtained for PE were 4.15 x 10(-5) min-1, 0.423 ml and 14.6 microliter min-1, respectively. The half-life for drug elimination ranged from 63-83 min depending on the tissue or route of administration.     

Influence of clofibrate on liver microsomal hydroxylation of cholesterol and androstenedione

The liver microsomal metabolism of 4-[4-¹⁴C]androstene-3,17-dione and [4-¹⁴C]cholesterol was studied in control and clofibrate-treated rats.In the control rat 25 per cent of androstenedione metabolites were hydroxylated at the 6β-position. Another 25 per cent were recovered as 16-oxygenated derivatives and minor amounts (5 per cent) were hydroxylated at the 6α- or a 7α-position. Clofibrate stimulated all the hydroxylation reactions of this compound. The 6β-hydroxylation was elevated by 100 per cent, the 7α-hydroxylation by 70 per cent, and the 6α- and 16α-hydroxylations by 50 per cent. Furthermore, following treatment with clofibrate, the ratio between 17β-hydroxy-4-androstene-3,16-dione and 16α-hydroxy-5-androstene-3, 17-dione increased from 0.15 to 0.68. The activity of the 17β-hydroxysteroid oxido-reductase increased by 100 per cent, whereas the 3β-hydroxysteroid oxidoreductase and 5α-reductase activities were only slightly affected.The 7α-hydroxylation of labelled cholesterol was uninfluenced by treatment with clofibrate.It is suggested that clofibrate stimulates the activity of the enzyme system involved in the hydroxylation of drugs in the liver.     

Shelf life of cefuroxime eye-drops when dispensed in artificial tear preparations

There has recently been a clinical demand for cefuroxime formulated as an eyedrop. Cefuroxime exhibits a broad spectrum of activity against most common ocular infections and is considered to be less toxic to the compromised epithelium than some other topical antibiotics. A formulation in an artificial tear solution would be expected to enhance drug penetration by prolonging pre-corneal drug retention, and the presence of a preservative might enable a suitable formulation to be given a shelf life of more than 24 hours. This paper reports studies on the stability of cefuroxime 50mg/ml (5 per cent) in artificial tear solutions, sodium chloride eye-drops and in solutions of benzalkonium chloride, hypromellose or water for injections. Cefuroxime was assayed by high performance liquid chromatography. The method had a coefficient of variation of 0.23 per cent at the concentration investigated and recovery of added cefuroxime was 100 per cent. The preparation of cefuroxime in artificial tear solutions which were preservative free or contained benzalkonium chloride less than 0.002 per cent appeared to be physically stable. Preparation of cefuroxime in Sno Tears also produced a stable solution. This preparation can be given a shelf life of 28 days at 4C, 24 hours at 25C and 14 days if stored in a domestic refrigerator, enabling a full course of treatment to be given on a single visit to the pharmacy.     

In vivo meal model for the evaluation of agents which affect the absorption of triglyceride and cholesterol

A meal model in which rats were trained to consume within 2 hr a high fat meal containing glycerol tri[1-¹⁴C]oleate and [³H]cholesterol was compared to the corn oil bolus model. In the meal model, dietary triglyceride was absorbed from the small intestine faster during the first 6–8 hr and more completely than intubated corn oil, as determined by analysis of intestinal contents, serum radioactivity, serum triglycerides, adipose tissue and liver lipids. The effects of Cholestyramine, Colestipol and Pluronic L-101 (1% dietary admixes) on these variables were evaluated for 5 days in the meal model. Lipid absorption during a 72-hr period was reduced by all compounds. The per cent excretion of glycerol tri[1-¹⁴C]oleate was increased significantly by Pluronic L-101 (10-fold), Cholestyramine (5.7-fold) and Colestipol (2.7-fold). The excretion of [³ H]cholesterol was enhanced significantly by Cholestyramine (1.6-fold) and Colestipol (1.3-fold). The following observations were made 4hr after the initiation of the meal. Pluronic L-101 increased significantly the retention of glycerol tri[1-¹⁴C]oleate and [³H]cholesterol in stomach (380 and 375 per cent, respectively), and of glycerol tri[1-¹⁴C]oleate in the small intestine (1100 per cent). The percent of intestinal lipid remaining as triglyce-ride from the intestinal lumen was increased significantly by Pluronic L-101 (160 per cent). Pluronic L-101 reduced significantly [¹⁴C]lipid and [³H]cholesterol in liver; Cholestyramine and Colestipol suppressed only [³H]cholesterol. In adipose tissue, Pluronic L-101 treatment reduced significantly [¹⁴C]lipid content only; Cholestyramine and Colestipol suppressed selectively [³H]cholesterol. After 5 days of treatment, only Pluronic L-101 treatment resulted in significantly reduced serum triglycerides (32 per cent), cholesterol (21 per cent) and glucose (15 per cent). These data suggest that this in vivo meal-feeding model provides a physiological technique for evaluating agents affecting lipid absorption.     

The reversibility of N-oxidation in vivo: The fate of 14C-N-hydroxychlorphentermine and 14C-nitrochlorphentermine in the rat

The interrelationships between primary amines and their in vivoN-oxidized metabolites are unclear. We have therefore synthesized ¹⁴C-N-hydroxychlorphentermine and ¹⁴C-nitrochlorphentermine and examined their metabolism and excretion in the rat. ¹⁴C-N-hydroxychlorphentermine was excreted slowly in the urine (66 per cent of dose in 6 days) with a further 8 per cent in the faeces (3 per cent) and as ¹⁴CO₂ (5 per cent), and the only urinary metabolites were the unchanged hydroxylamine and its glucuronic acid conjugate. ¹⁴C-Nitrochlorphentermine was eliminated more rapidly (92 per cent of dose in 4 days), with 41 per cent in the urine, 1 per cent in the faeces and 50 per cent as ¹⁴CO₂. The only urinary metabolites were the reduction product N-hydroxychlorphentermine and its glucuronide but the large amount of ¹⁴CO₂ found indicated that side chain oxidation was a major metabolic route. The results are discussed with reference to the possible reversibility of N-oxidation in vivo and putative mechanisms for the oxidation of the side chain.     

Perceptions of preregistration graduates about the UK pharmacy undergraduate course

This study reports on the perceptions of recent graduates of their undergraduate pharmacy course. Questionnaires were sent to 952 graduates undertaking their preregistration training in the period 1992–3. Of the total response of 695 (73 per cent), 55 per cent were in community pharmacy, 38 per cent in hospital and the remainder in various joint posts. Their opinions on the usefulness of course topics indicated that pharmacognosy and some topics within pharmaceutical chemistry were significantly regarded as of little use (P<0.05), while the vocationally-oriented topics were the most useful. The only topics thought to require significantly more extensive teaching (P<0.05) were responding to symptoms and clinical pharmacy. Pharmacognosy and some topics within pharmaceutical chemistry were considered to require less teaching. The remainder were considered to be given sufficient time. Problem-solving, and small group tutorials and seminars were considered very useful forms of learning by 73 per cent and 63 per cent of respondents, respectively. Clinically-oriented topics were considered significantly beneficial (P<0.05) and useful for inclusion within the new four-year framework. The study suggests that changes in course design should not include undergraduate specialisation, the graduates' branch of pharmacy having no influence on their opinion of the usefulness of clinical pharmacy and pharmacy practice topics. It also suggests that some science-based topics need to be made more relevant to pharmacy and that clinical and practice-based topics should have a major role in an extended course.     

Treatment of inflammatory and paraproteinemic neuropathies

Acquired demyelinating and inflammatory neuropathies encompass a number of acute and chronic autoimmune conditions characterized by variable degrees of clinical involvement. These disorders, including Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN), and paraprotein-associated neuropathy, have an overall annual incidence of 2-4/100,000 worldwide and are potentially treatable. Over the last few years, several investigations have helped clarify the pathogenesis of immune neuropathies and the definition of molecular targets involved in these diseases, thus providing firmer grounds for treatment with classical immunosuppressive drugs and new biological agents. In GBS and related variants, which are characterized by cellular inflammation and alterations of the blood-nerve barrier, randomized clinical trials show that plasma exchange (PE) and intravenous immunoglobulin (IVIg) are equally effective as disease-modifying treatments, although IVIg has been adopted as the favourite treatment in most centres. In CIDP, controlled clinical trials have established the efficacy of oral prednisone, PE and IVIg, with intermittent IVIg treatment or corticosteroids being usually preferred. Adding azathioprine can help keep lower the required dose of prednisone, while other immunosuppressive agents, such as cyclophosphamide and cyclosporin A may have side effects, limiting their use to selected cases. Currently, the efficacy of interferon beta and alfa is under evaluation. Controlled trials support the view that IVIg is the treatment of choice in MMN. Patients resistant to IVIg administration may benefit of treatments which deplete B cells, such as cyclophosphamide and rituximab. Demyelinating neuropathies associated with circulating paraproteins are clinically heterogeneous, depending on the reactivity and type of the monoclonal (M) protein. In many cases, neuropathies associated with IgM M proteins are not treated because of their slow progression. In patients with a disabling or rapid progression, small trials have shown short-term benefits from IVIg or PE. Recently, fludarabine and rituximab have been reported as beneficial in selected cases.     

Time course of the induction of aryl hydrocarbon hydroxylase in rat liver nuclei and microsomes by phenobarbital, 3-methylcholanthrene, 2,3,7,8-tetrachloro-dibenzo-p-dioxin,dieldrin and other inducers

Aryl hydrocarbon hydroxylase (AHH) has been measured in male rat liver nuclei and microsomes after treatment of adult animals with various inducers for up to 14 days. After daily i.p. injections of 3-methylcholanthrene (MC, 20 mg/kg) the nuclear activity increased to a maximum of 600 per cent of the control activity after 4 days whereas the microsomal activity was 400 per cent of control at the same date. After 12 days, both activities equilibrated at 400 per cent. A similar time course was found after a single i.p. injection of 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD, 0.01 mg/kg) with an induction to 500 and 300 per cent for nuclei and microsomes, respectively, after 2 days, and to 400 per cent for both after 12 days. Phenobarbital (PB) was given continuously in the drinking water (1 g/l) and induced the microsomal activity to 200 per cent after 8 days and 170 per cent after 14 days. the nuclear activity was only slightly induced to a Constant level of 130 per cent between day 8 and 14. Dieldrin did not significantly increase the microsomal activity after daily i.p. injections (20 mg/kg), but the nuclear activity raised to 200 per cent after 3 days and levelled down to control values after 12 days. Other inducers tested were benz[a]anthracene (BA), hexachlorobenzene (HCB) and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT). The induction pattern with BA was similar to that of MC, a model compound for the group of cytochrome P448 inducers. the induction by HCB and DDT resembled that by PB, a typical cytochrome P450 inducer.     

Empiric therapy for treatment of infection and the influence of antibiotic guidelines on outcomes

The appropriateness of empiric therapy, how closely prescribers adhered to hospital guidelines for use of antimicrobial drugs and how relevant these guidelines proved in providing cover for the infecting pathogen were assessed from a retrospective survey of culture and sensitivity reports issued during a one-month period in a district general hospital. Blood, stool, pus, sputum and mid-stream urine specimens were reviewed. Urine specimens from a fundholding general practice unit were also included. Catheter specimens of urine and specimens from other body sites were excluded. Of 290 specimens sent for culture, 99 (34 per cent) were positive. One hundred patients, of whom 54 (19 per cent of the total) were subsequently demonstrated to have a positive culture, had been treated empirically. In 38 per cent of cases the pre-report empiric treatment was considered appropriate for the isolated pathogen, while 46 per cent of patients had negative cultures and 16 per cent had positive cultures but had been given unsuitable antibiotics. In hospitalised patients, 73 per cent of antibiotic treatments were prescribed according to hospital guidelines, although this was the case for only 45 per cent of community-based patients. Hospital guidelines were a relevant and useful aid to rational prescribing in that 75 per cent of organisms isolated were sensitive to guideline antibiotics. The guidelines were least appropriate for urine specimens from hospital. This reflects the range of organisms encountered and the emergence of resistant strains, reinforcing the need for regular updating and amending of prescribing recommendations.     

Metabolism of 14C-2',3'-dideoxyinosine by the in situ perfused rat liver preparation

The metabolism and biliary excretion of 14C-dideoxyinosine (14C-ddI) has been investigated using the in situ perfused rat liver (PRL) preparation. After 2 h of perfusion through the liver, approximately 70-75 per cent of the total 14C-radiolabel was recovered in the perfusion medium, less than 1 per cent was excreted in bile and 15-18 per cent was retained in the liver. Hepatic clearance of ddI was 1.5 +/- 0.1 ml min-1 and half-life for the elimination of ddI from the medium was 22.9 +/- 2.0 min (n = 3). Hepatic extraction was estimated to be 7.5 per cent. HPLC analysis of the effluent perfusate indicated that ddI was metabolized to hypoxanthine, xanthine, uric acid, and to a polar metabolite which was tentatively identified as allantoin. Approximately 60-65 per cent of the ddI dose was converted to allantoin after 2 h of perfusion. Of the other three metabolites, uric acid levels increased to 20-30 per cent of the dose after 45 min and declined to about 5 per cent of the dose by the end of the perfusion period. Levels of hypoxanthine and xanthine were low and both compounds were not detected in the perfusate after 45 min post-infusion. In bile, the major peak, which accounted for about 50 per cent of the 14C-radiolabel co-eluted with the putative metabolite, allantoin (0.4 per cent of the dose). Uric acid (0.06 per cent of the dose) was the only other metabolite detected in bile. These results suggest that biliary excretion is a minor pathway for the elimination of ddI. Furthermore, ddI is rapidly cleared and metabolized by the liver to hypoxanthine, xanthine, uric acid, and to allantoin.