Acute tubulointerstitial nephritis associated with antineutrophil cytoplasmic antibody following cimetidine treatment: a case report.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis usually induces rapidly progressive glomerulonephritis, including pauci-immune necrotizing crescentic glomerulonephritis. Acute tubulointerstitial nephritis (ATIN), which is often drug-induced, is a frequent cause of kidney injury. However, ATIN associated with ANCA without any glomerular lesions has been rarely reported, and drug-induced ATIN associated with ANCA is not well recognized. Here we present a case of an older woman with ATIN associated with myeloperoxidase-ANCA (MPO-ANCA) following cimetidine treatment. CASE PRESENTATION: A 70-year-old woman was admitted to our hospital due to acute kidney injury and mild proteinuria. She had a one-year history of chronic thyroiditis and dyslipidemia, for which she was taking levothyroxine sodium and atorvastatin, respectively. Two weeks before admission she had started cimetidine, methylmethionine sulfonium chloride, and itopride hydrochloride for gastric discomfort persistent since a month. She had experienced fatigue for two weeks and later appetite loss. The patient demonstrated a positive titer for MPO-ANCA (192 IU/mL) and a positive drug-induced lymphocyte stimulation test for cimetidine. She underwent two kidney biopsies that revealed ATIN without any glomerular lesions. Despite discontinuation of cimetidine on admission, renal injury continued with the presence of high MPO-ANCA titer. Oral steroid treatment was closely related with the recovery of her renal function and disappearance of MPO-ANCA. CONCLUSIONS: In this case, ATIN presented as sustained renal insufficiency and high MPO-ANCA titer despite withdrawal of cimetidine. Therefore, we reason that the development of ANCA-associated ATIN was caused by cimetidine. Serologic follow-up with measurement of MPO-ANCA titers and renal biopsy are recommended when the clinical history is inconsistent with the relatively benign course of drug-induced ATIN.

Avaliação da atividade protetora gástrica do extrato hidroalcoólico da semente de girassol em ratas / Evaluation of the gastroprotective activity of hydroalcoholic extract of sunflower seed in rats

JUSTIFICATIVA E OBJETIVOS: Avaliar a proteção gástrica do extrato hidroalcoólico da semente de girassol (EHSG) em relaçãoao estresse, ao uso de indometacina e etanol. MÉTODO: Foi realizado um estudo experimental envolvendo 90 ratas (Rattus norvegicus albinus), da linhagem Wistar, fêmeas, com peso corporal médio de 150-230 g, divididos em 18 grupos distintos os quais receberam os seguintes tratamentos: EHSG:250 mg/kg, 500 mg/kg, 1000 mg/kg e 2000 mg/kg; etanol 0,5mL; cimetidina 60 mg/kg; indometacina 20 mg/kg; água 1 mL. Os dados foram analisados utilizando o programa Grand PadPrism 5 com aplicação de testes estatísticos considerando o nível de significância de 5%. RESULTADOS: O EHSG apresenta proteção contra as lesões gástricas em ratas, nas doses de 250 e 1000 mg, tanto no modelo pelo estresse, quanto na indução por etanol e indometacina. CONCLUSÃO: Os dados obtidos no presente estudo mostram que o EHSG apresenta proteção gástrica em determinadas doses.

BACKGROUND AND OBJECTIVES: To evaluate the gastric protection hidroalcoólico extract the sunflower seed (EHSG) in relation to stress, the use of indomethacin and ethanol. METHOD: We conducted an experimental study involving 90 rats (Rattus norvegicus albinos), Wistar, females, mean body weight of 150-230 g were divided into 18 distinct groups which received the following treatments: EHSG: 250mg/kg , 500 mg/kg, 1000 mg/kg and 2000 mg/kg; 0.5 mL ethanol, cimetidine 60 mg/kg, 20 mg/kg indomethacin; 1 mL water. Data were analyzed using the GrandPad Prism 5 with application of statistical tests, the significance level of 5%. RESULTS: The EHSG has protective against gastric injury in rats at doses 250 mg and 1000, both in the model by stress, as in the induction by ethanol and indomethacin. CONCLUSION: The data obtained in this study show that has EHSG gastric protection in certain doses.

H2 blockers decrease gut mucus production and lead to barrier dysfunction in vitro.

BACKGROUND: Pneumonia and other gut-related infectious complications have been associated with the use of histamine 2 (H2) receptor antagonists such as cimetidine in critically ill patients. The mechanism(s) may include acid suppression with resultant effects on the gut flora. Other possibilities include immunologic effects and perturbation of gut barrier function. Recent work has demonstrated the importance of mucus on the gastrointestinal mucosal barrier. We studied the effect of cimetidine on mucus production and mucosal barrier function in vitro. METHODS: HT29-MTX, a mucus-producing intestinal epithelial cell line, was used. HT29-MTX cell monolayers were grown to confluence in the presence of cimetidine for 0, 3, or 6 days. Mucus production was quantified by Western Blot analysis and O-linked oligosaccharide chain release and mucin content by enzyme-linked immunosorbent assay. Fluorescein-labeled Escherichia coli (EC) or unlabeled EC were added to quantify bacterial adherence (60-min co-culture) and passage thru HT29-MTX cell monolayers (120-min co-culture), respectively. RESULTS: Cimetidine treatment decreased mucus/mucin content after 3 or 6 days of treatment. The effect was more profound after 6 days. There was nearly a 2-fold increase in passage of EC across HT29-MTX monolayers after cimetidine treatment. CONCLUSION: Cimetidine seems to contribute to gut barrier dysfunction by its effect on mucus production. This study supports the increasing clinical suspicion that routine administration of H2 blockers in critically ill patients may be ill advised.

[Drug-induced tremor]. / Medikamentös-induzierter Tremor.

Drug-induced tremor is an important differential diagnosis for tremor syndromes. In view of a constantly ageing population and increasingly frequent polypharmacotherapy, identification of potentially tremor-inducing drugs may help generating risk profiles for individual patients. Drug-induced tremor has often been seen as a complication of antipsychotic therapy, but its occurrence has also been described in response to a great diversity of compounds such as antidepressants, sympathomimetics, antiarrhythmics, antiepileptics and other drugs. The present article presents a synopsis of the most prevalent tremor-inducing drugs as well as strategies to overcome drug-induced tremor, either by replacement of the causative drug or by symptomatic therapies.

The safety of H(2)-blockers use during pregnancy.

Little data exist on the safety of H(2)-blockers during pregnancy. A computerized database of medications dispensed from 1998 to 2007 to all women registered in the "Clalit" health maintenance organization, in the Southern District of Israel, was linked with computerized databases containing maternal and infant hospitalization records from the district hospital. The following confounders were controlled for: parity, maternal age, ethnic group, maternal diabetes, smoking, and peripartum fever. Also, therapeutic pregnancy termination data were analyzed. A total of 117 960 infants were born during the study period, 84 823 of them (72%) to women registered at Clalit; 1148 of the latter were exposed to H(2)-blockers during the first trimester of pregnancy. Exposure to H(2)-blockers was not associated with an increased risk for congenital malformations (adjusted odds ratio [OR] = 1.03, 95% confidence interval [CI]: 0.80-1.32); also, no such association was found when therapeutic pregnancy terminations were included in the analysis (adjusted OR = 1.17, 95% CI: 0.93-1.46). Exposure to H(2)-blockers was not associated with perinatal mortality, premature delivery, low birth weight, or low Apgar scores.

Immune hemolytic anemia due to cimetidine: the first example of a cimetidine antibody.

BACKGROUND: Although there have been a few reports of immune hemolytic anemia (IHA) thought to be due to cimetidine, none of them provided proof (e.g., serologic detection of anti-cimetidine and/or repeat of IHA upon drug rechallenge). One report used cimetidine as an example of how temporal associations of drug administration and hemolytic anemia are not proof of a cause-effect relationship. STUDY DESIGN AND METHODS: A 63-year-old cancer patient developed IHA on two occasions after receiving cimetidine (with and without chemotherapy). Serologic methods included testing cimetidine-treated red blood cells (RBCs) as well as testing untreated RBCs in the presence of cimetidine. RESULTS: The patient's direct antiglobulin test was positive (C3 only) and a serum antibody to cimetidine was detected by both testing methods. An eluate from the patient's RBCs was nonreactive. Cimetidine-treated RBCs were optimally prepared at room temperature and needed to be tested on the day of preparation. CONCLUSIONS: This is the first reported case of IHA due to a cimetidine antibody where a drug-dependent antibody was demonstrated. The patient had IHA after receiving cimetidine on two separate occasions.

Cimetidine use and the risk for prostate cancer: results from the VITAL cohort study.

PURPOSE: The histamine-2 (H(2)) blocker cimetidine may alter androgen, zinc, and prolactin levels, which could alter prostate cancer risk. Increased risk for men filling more than 20 cimetidine prescriptions was reported previously. We examined the association between cimetidine use and prostate cancer risk in a cohort in western Washington State. METHODS: Participants were 33,506 men, 50 to 76 years old, enrolled in the VITamins And Lifestyle cohort (VITAL). H(2)-blocker use during the prior 10 years was self-reported through baseline questionnaire between October 2000 and December 2002. Men were followed up for subsequent prostate cancer by linkage to the Surveillance, Epidemiology and End Results cancer registry. We identified 548 incident invasive prostate cancer cases diagnosed from baseline to December 31, 2003. RESULTS: Overall, no association between ever use of cimetidine or years of cimetidine use and prostate cancer risk was observed. However, daily cimetidine use for 10 years was associated with increased risk (relative risk, 2.35; 95% confidence interval, 1.05-5.26) compared with nonuse of any H(2) blockers. Use of other H(2) blockers was not associated with prostate cancer. CONCLUSIONS: Additional studies are needed to determine whether long-term daily cimetidine use is associated with increased prostate cancer risk in other populations, and if so, the reason for this association.

[Safety of proton pump inhibitors]. / Seguridad de la utilización de los inhibidores de la bomba de protones.

The significant inhibitory capacity of gastric acid secretion of PPIs makes them the drugs of choice for treating acid-related diseases. The considerable prevalence of these diseases and the need for maintaining the administration of the drug during considerably long periods results in this therapeutic group being one of the most widely used. However, in spite of their extensive use, there continue to emerge concerns about their potential toxicity; concerns surrounding the specificity of their mechanism of action and a consequential suspicion that something so potent must involve harmful effects. PPIs act selectively on the final stage of the process of gastric acid secretion, namely the H+/K+-ATPase or proton pump. This enzyme represents an essential step in the process of secretion of H+, and PPIs exert a very specific action on the parietal cell, as they need an environment with very low pH levels, which only exist in this cell. In the present article, the adverse effects of PPIs are reviewed, with special emphasis on those related to their continued administration and on the special circumstances of patients, as in the case of the elderly, those with liver failure, pregnant and breastfeeding mothers and children. All the PPIs on the market share a common chemical basis and there are no great differences in their potential adverse effects, the possibility of them promoting opportunist infections or their capacity to generate pharmacokinetic interactions with other drugs, which, if occur, are generally insignificant. After two decades of use, PPIs have proved to be very effective and safe drugs.

Cimetidine-induced tubulointerstitial nephritis with both MPO-ANCA and PR3-ANCA.

We describe a 75-year-old man with tubulointerstitial nephritis (TIN) with myeloperoxidase (MPO)-antineutrophil antibody (ANCA) and proteinase-3 (PR3)-ANCA. He had a slight fever and eruption with itching after taking cimetidine (prescribed after gastrectomy for gastric cancer) and he was admitted to a nearby hospital. There, he showed proteinuria, serum creatinine (sCr) of 2.9 mg/dl, and creatinine clearance (Ccr) of 44 ml/min per 1.73 m2. His MPO-ANCA titer was 267 EU, and PR3-ANCA titer was 112 EU. Abnormal concentrations in bilateral kidneys were found by gallium scintigraphy. For these reasons, he was transferred to our hospital. Percutaneous renal biopsy was performed after admission. Severe tubular atrophy, mild interstitial fibrosis, and severe mononuclear cell infiltration of the interstitium were noted. Drug-induced renal impairment was suspected, and cimetidine administration was withdrawn. Lymphocyte stimulation tests (DLSTs) were performed. The cimetidine titer was positive, at 2,537 cpm. After the withdrawal of cimetidine, the PR3-ANCA titer was reduced gradually, and, next, the MPO-ANCA titer was also reduced. The sCr level was reduced to 1.2 mg/dl. In summary, we report herein the first case of cimetidine-induced TIN associated with both MPO-ANCA and PR3-ANCA.

Adverse haematological effects of vinblastine, prednisolone and cimetidine treatment: a retrospective study in fourteen dogs with mast cell tumours.

Vinblastine toxicity is poorly documented in dogs. The aim of this study was to investigate the haematological alterations in dogs treated with vinblastine and prednisolone. Fourteen dogs with mast cell tumours (MCT) were selected on at least one of the following criteria: lymph node infiltration, surgical margin infiltration, grade II MCTs with Ki-67 >10%, and grade III MCTs. Starting 15 days after surgery, the dogs were given vinblastine (2 mg/m2 i.v. four times weekly, then twice monthly for 2 months) and prednisolone (2 mg/kg/day p.o.). An EDTA blood sample was collected weekly for complete blood count (CBC). A total of 98 doses of vinblastine were given to the 14 dogs and 114 CBC were performed. Abnormal haematological findings were observed in 12 CBCs from five dogs, which represent a prevalence of 20% of the total CBCs performed in these animals. The most prevalent abnormal finding was thrombopenia (9/12) most often with grade I toxicity (6/9). In conclusion, the risk of occurrence of adverse haematological effects resulting from vinblastine-prednisolone treatment seems limited in dogs with MCT and it should not be overestimated.

Randomized, double-blind study comparing postoperative effects of treatment timing with histamine H-receptor antagonist cimetidine.

BACKGROUND: The purpose of this study was to evaluate the effect of timing of preoperative, postoperative, and placebo administration of the H(2)-antagonist cimetidine on postoperative pain management and the incidence of side-effects. METHODS: One hundred and twenty ASA I to II patients, undergoing major gynaecological abdominal surgery, were randomly divided into three groups, and received a standardized general anaesthesia. The patients in the preoperative ('Pre') group received an intravenous infusion of cimetidine 4 mg kg(-1) prior to anaesthesia induction; the postoperative ('Post') group received the same volume of normal saline. Postoperatively, the patients in the Post group received an intravenous infusion of cimetidine 4 mg kg(-1); the patients in the Pre group received the same volume of normal saline. The Control group received the same volume of normal saline prior to anaesthesia induction and after the end of operation. Postoperatively, all patients were treated with a patient-controlled intravenous analgesia system, which was programmed to deliver 1 mg of morphine on demand for three consecutive days. RESULTS: Pain intensity, morphine consumption, sedation score, and side-effects were recorded and evaluated. We found no difference among the three groups with respect to pain intensities, morphine usage, sedation scores, and the incidence of nausea, vomiting, pruritus, or dizziness. CONCLUSIONS: Our results suggested that neither preoperative nor postoperative administration of cimetidine 4 mg kg(-1) provided a pre-emptive or preventive analgesic advantage for postoperative pain or morphine consumption, and that the use of cimetidine failed to reduce the incidence of nausea or vomiting.

Cimetidine and other histamine2-receptor antagonist use in relation to risk of breast cancer.

OBJECTIVE: Cimetidine, a histamine2-receptor antagonist (H2 blocker) commonly used to treat symptoms of peptic and duodenal ulcer, influences both hormonal and immune pathways. We investigated the influence of cimetidine use on the risk of breast cancer in our hospital-based case control surveillance study. METHODS: Data on medication use and other factors were elicited from patients admitted to hospitals from 1977 to 2002. We compared 6,994 breast cancer cases with a control group comprising cancer (n = 2,478) and noncancer (n = 6,004) diagnoses. Conditional logistic regression models were used to estimate odds ratios for H2 blocker use that began at least 1 year prior to admission. Regular use was defined as use for at least 4 days per week for at least 3 continuous months. RESULTS: The odds ratio for breast cancer among regular users of cimetidine was 0.9 (95% confidence interval, 0.6-1.2) using a combined cancer and noncancer control group. For use of 4 or more years' duration, the odds ratio was < 1.0 but was not statistically significant. The odds ratio for the regular use of other H2 blockers was 0.9 (95% confidence interval, 0.6-1.3). CONCLUSIONS: Our data agree with data from three prior studies which indicate that cimetidine is not associated with the risk of breast cancer. Other H2 blockers were also unrelated to the risk of breast cancer.

The effect of H2-receptor antagonist and proton pump inhibitor on microbial proliferation in the stomach.

BACKGROUND/AIMS: Intra-gastric bacterial proliferation is frequent in patients with hypochlohydria. However, status of gastric bacterial infection in patients receiving proton pump inhibitor or H2-receptor antagonist remains controversial. The purpose of this study was to investigate the microbial condition of the stomach in patients who received H2-receptor antagonist or proton pump inhibitor. METHODOLOGY: Between November 2000 and January 2002, 102 patients were enrolled in this study. Of these, 52 did not receive any treatment (group I), 26 received H2-receptor antagonist (group II), and 24 received proton pump inhibitor (group III). Ten mL of gastric juice were aspirated for culture during endoscopic examination. The aerobic and anaerobic bacterial and fungal cultures were performed immediately. A glass pH meter measured the pH of the gastric juice. RESULTS: The intra-gastric pH was 2.91+/-2.06 (mean +/- SD), 4.12+/-2.83, and 5.11+/-2.47 for groups I, II, and III, respectively (p=0.001 between groups I and III, p>0.05 between groups I and II, and groups II and III). The positive bacterial culture rates were 66.7% (16/24) in group III, 46.2% (12/26) in group II, and 28.8% (15/52) in group I (p=0.007 between groups III and I,p>0.05 between groups I and II, and groups II and III). The positive candidal culture rates were 12.5% (3/24) in group III, 11.5% (3/26) in group II, and 17.3% (9/52) in group I (p>0.05). CONCLUSIONS: Patients who received proton pump inhibitor had more acid suppression and intra-gastric bacterial infection than those of the control group. The intra-gastric candidal infection was not related to intra-gastric pH or anti-secretory medication in this study.

Treatment of human solid malignancies with autologous activated lymphocytes and cimetidine: a phase II trial of the cancer biotherapy research group.

OBJECTIVE: The Cancer Biotherapy Research Group conducted a clinical trial to verify encouraging reports of antitumor activity of autolymphocyte therapy. PATIENTS AND METHODS: Patients with a variety of advanced solid malignancies underwent an initial leukapheresis procedure to collect about 5 x 10(9) autologous lymphocytes that were stimulated in vitro for 3 days with anti-CD3 monoclonal antibody in the presence of indomethicin and cis-retinoic acid to obtain media that was frozen in aliquots. This media contained significant amounts of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon-gamma, and IL6, but no IL-2. Subsequently patients underwent up to 6 monthly leukaphereses to collect 2-5 x 10(9) autologous lymphocytes that were incubated in vitro for 6 days in the cryopreserved media containing autologous lymphokines, resulting in a cell population enriched for noncytotoxic T-helper lymphocytes. These were administered intravenously monthly for up to 6 months with daily oral cimetidine at a dose of 600 mg po qid, which was given throughout the treatment period. Tumor response was assessed every 2 months. RESULTS: There were 47 patients (25 women and 22 men) with a median age of 55 years (range 31-79). One hundred seventy four treatments were delivered and were well tolerated. A mean of 2.05 +/- 1.46 (range 0.82-12.8 x 10(9)) cells were infused. Eighty-five percent received two or more doses; 19% received six doses. Objective tumor responses were observed in 1/15 renal cell, 1/13 colorectal, 0/6 breast, 0/5 lung, 0/2 gastric, 0/2 sarcoma, 0/1 pancreas, 0/1 prostate, 0/1 melanoma, and 0/1 eccrine. Forty-three patients have died. Median survival was 8.8 months, 1-year survival 35%, and 2-year survival 15%. CONCLUSION: This complex treatment program was feasible. Infusion of these cells was well tolerated. Some antitumor activity was seen in patients with renal cell cancer and colorectal cancer.

A review of epidemiological studies on cancer in relation to the use of anti-ulcer drugs.

H2-receptor antagonists have been widely used since the late 1970s for the treatment of gastrointestinal ulcers and other benign conditions of the stomach, oesophagus and duodenum. Several case reports suggested that long-term therapy with H2-receptor antagonists, mainly cimetidine and ranitidine, might increase the risk of gastric cancer. After early case reports, at least six analytical epidemiological studies (two cohort and four case-control) were published, including a total of about 1000 cases of gastric cancer. The relative risks (RR) were systematically and substantially elevated in the first year since starting H2-receptor antagonist use, and levelled off in the following years. Some excess risk was still apparent during the first 5 years of drug use, probably due to incorrect diagnosis and treatment of pre-existing neoplastic gastric lesions, but the estimated RR was not above unity for > or = 10 years since starting drug treatment in the two studies including information on long-term use. The findings of analytical epidemiological studies are thus consistent with the absence of a causal association between H2-receptor antagonist use and gastric cancer risk. Data on oesophageal and colorectal cancer do not support a relevant relation between cimetidine use and the risk of these neoplasms. With reference to total cancer mortality, in a Danish cohort study, for males the RR was 1.9 in the first year, and 1.4 in the first 5 years; corresponding values for females were 1.7 and 1.5. In a British cohort study, the RR was 3.4 in the first year, and 1.3 in the years 2-10. The excess risk in the first year was essentially due to gastric cancer. Post-marketing surveillance data for omeprazole and other proton pump inhibitors are much scantier than for H2-receptor antagonists, particularly on long-term use.

Nephrotoxicity and hepatotoxicity of histamine H2 receptor antagonists.

The extensive use of selective histamine H2 receptor antagonists provides a unique opportunity to describe very rare adverse drug reactions. Although mild elevation of serum creatinine level following the administration of cimetidine is relatively common, acute interstitial nephritis (AIN) is a rare hypersensitivity reaction. There have been 25 published reports of AIN associated with H2 antagonist therapy and we also identified 16 cases from the Australian Adverse Drug Reaction Advisory Committee (ADRAC) database. AIN was reported most commonly following cimetidine administration. AIN was supported by renal biopsy in 28 patients and by rechallenge in 6. H2 antagonist-induced AIN was more commonly reported in men older than 50 years. In the majority of cases the onset was within 2 weeks of initiation of therapy (1 day to 11 months). The clinical manifestations were nonspecific including sterile pyuria, elevated erythrocyte sedimentation rate, fatigue, proteinuria and leucocytosis whereas rash, arthralgia and flank pain were rarely reported. There were 170 cases of hepatotoxicity following H2 antagonist administration reported to ADRAC. These were more common following ranitidine and included cholestatic, hepatocellular and mixed reactions. Hepatotoxicity was proven following liver biopsy in several cases published in the literature and in 15 cases reported to ADRAC. Hepatotoxicity recurred upon rechallenge in 6 cases. Generally, renal and hepatic adverse effects resolved quickly after cessation of H2 antagonist therapy and did not require specific treatment. Nephrotoxicity and hepatotoxicity following administration of an H2 antagonist is rare and a high index of suspicion is necessary for early detection. Now that many H2 antagonists are available over the counter, awareness of these conditions and early detection with cessation of H2 antagonist therapy would appear paramount.

High-dose cimetidine reduces proinflammatory reaction after cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Cimetidine, which is usually used for gastric ulcer, enhances cellular immunity. The effect of cimetidine on perioperative proinflammatory response after cardiac surgery with cardiopulmonary bypass was investigated. METHODS: Elective coronary artery bypass graft cases in which CPB was performed were placed randomly in a cimetidine (C) group (n = 20) or a no-treatment (N) group (n = 20). The time course of plasma levels of neutrophil elastase, interleukin (IL)-6 and IL-8, leukocyte counts, lymphocyte recovery ratio, C-reactive protein, creatine-kinase-MB, and oxygenation index were analyzed. RESULTS: The plasma levels of neutrophil elastase and IL-8 were inhibited in the C groups at 2 hours after CPB termination. In a comparison of the two groups, the C group demonstrated higher lymphocyte recovery ratio and lower C-reactive protein on postoperative day 5 and shorter intubation time. No intergroup differences were observed in IL-6, leukocyte counts, creatine-kinase-MB levels, or oxygenation index. CONCLUSIONS: Cimetidine may reduce surgical stress and augment the immune system after cardiac surgery with cardiopulmonary bypass.

Studies on the interactions between drugs and estrogen: analytical method for prediction system of gynecomastia induced by drugs on the inhibitory metabolism of estradiol using Escherichia coli coexpressing human CYP3A4 with human NADPH-cytochrome P450 reductase.

To establish a prediction system for drug-induced gynecomastia in clinical fields, a model reaction system was developed to explain numerically this side effect. The principle is based on the assumption that 50% inhibition concentration (IC(50)) of drugs on the in vitro metabolism of estradiol (E2) to its major product 2-hydroxyestradiol (2-OH-E2) can be regarded as the index for achieving this purpose. By using human cytochrome P450s coexpressed with human NADPH-cytochrome P450 reductase in Escherichia coli as the enzyme, the reaction was examined. Among the nine enzymes (CYP1A1, 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) tested, CYP3A4 having a V(max)/K(m) (ml/min/nmol P450) value of 0.32 for production of 2-OH-E2 was shown to be the most suitable enzyme as the reagent. The inhibitory effects of ketoconazole, cyclosporin A, and cimetidine toward the 2-hydroxylation of E2 catalyzed by CYP3A4 were obtained, and their IC(50) values were 7 nM, 64 nM, and 290 microM, respectively. The present results suggest that IC(50) values thus obtained can be substituted as the prediction index for gynecomastia induced by drugs, considering the patients' individual information.