Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

At least 19 recordsLinked to original sources

PubMed2001

Minimal in vivo activation of CYP2C9-mediated flurbiprofen metabolism by dapsone.

Dapsone has been shown to activate flurbiprofen 4'-hydroxylation by expressed CYP2C9 enzyme and in human liver microsomes. It has been suggested that this observation is due to substrate cooperativity on enzyme activity; however, the in vivo relevance of this observation is unknown. Thus, the purpose of this study was to evaluate whether dapsone can act cooperatively with flurbiprofen to activate the in vivo metabolism of flurbiprofen to 4'-hydroxyflurbiprofen. Twelve healthy subjects received single-dose flurbiprofen 50 mg on three occasions: alone (visit A); 2 h after a single dapsone 100-mg dose (visit B); and 2 h after the seventh daily dose of dapsone 100 mg (visit C). Concentrations of flurbiprofen and 4'-hydroxy flurbiprofen in plasma and urine and dapsone and N-acetyldapsone in plasma were determined by HPLC. Flurbiprofen pharmacokinetic parameters for the three visits were estimated by non-compartmental methods and compared in the absence and presence of dapsone. Flurbiprofen apparent oral clearance was increased by approximately 11% (P < 0.02) after dapsone 100 mg for 7 days. Dapsone plasma concentrations averaged 5 +/- 2 microM after a single dose and 11 +/- 4 microM after seven daily 100 mg doses. These dapsone plasma concentrations were within the range of concentrations producing activation of flurbiprofen metabolism by CYP2C9 in vitro. These results are consistent with the hypothesis that dapsone does influence flurbiprofen metabolism in vivo in a cooperative way to enhance metabolism. However, the magnitude of effect is substantially less than observed in vitro.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2001

Lack of tacrolimus-induced cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) has been reported in pediatric transplant patients receiving tacrolimus. It is unclear whether tacrolimus is associated with HCM in adult transplant recipients. OBJECTIVE: To determine the prevalence of HCM in noncardlac adult transplant patients receiving tacrolimus. METHODS: A retrospective analysis of nonheart transplant recipients who received tacrolimus at our institution from January 1982 to April 1996 was conducted. Patients with left-ventricular hypertrophy (LVH) defined as a posterior or septal wall thickness > or = 1.3 cm by echocardiography (ECHO) were independently evaluated. RESULTS: There were 3609 patients who met entry criteria including 2257 liver, 1333 kidney, and 19 other organ transplants. Of the 502 patients who had undergone ECHOs after transplantation, 171 had LVH. The etiology of LVH was categorized as valvular disease (36%), hypertensive disease (29%), ischemic heart disease (17%), or multifactonal (15%). There were six patients in whom, after detailed chart review, no underlying cause of LVH was evident. Five of these patients had HCM, representing an overall prevalence of 0.1% in the entire group of tacrolimus-treated patients, and 1% in patients referred for ECHO. CONCLUSIONS: The prevalence of HCM in our tacrolimus-treated adult transplant population is similar to that reported in general population studies. These data suggest that tacrolimus is not a risk factor for HCM in adult transplant recipients.

Adult↗

PubMed2001

Prevalence and risk of thrombocytopenia with valproic acid: experience at a psychiatric teaching hospital.

STUDY OBJECTIVE: To investigate the prevalence and potential risk factors of thrombocytopenia in hospitalized patients receiving valproic acid (VPA) for psychiatric indications (excluding epilepsy). DESIGN: Retrospective study SETTING: University-affiliated psychiatric facility. PATIENTS: Two hundred sixty-four patients treated with VPA. INTERVENTION: Data from patients hospitalized between January 1, 1994, and December 31, 1998, who were receiving VPA and had at least one platelet count recorded. MEASUREMENTS AND MAIN RESULTS: Of 264 VPA-treated patients, 31 (12%) met our criteria for thrombocytopenia. Mild thrombocytopenia (platelet count of 101-150 x 10(3)/mm3) occurred in 25 (9%) patients, and moderate thrombocytopenia (platelet count of 40-100 x 103/mm3) occurred in 6 (2%) patients. Age older than 65 years (p=0.02) and VPA dosage greater than 1,000 mg/day (p<0.001) were identified as significant risk factors for developing thrombocytopenia. CONCLUSION: The estimated prevalence of thrombocytopenia is 12% in the general psychiatric population receiving VPA, with the elderly at greatest risk.

Adolescent↗

PubMed2000

Changing physician prescribing behavior: the community-acquired pneumonia intervention trial.

The Notes section welcomes the following types of contributions: (1) practical innovations or solutions to everyday practice problems, (2) substantial updates or elaborations on work previously published by the same authors, (3) important confirmations of research findings previously published by others, and (4) short research reports, including practice surveys, of modest scope or interest. Notes should be submitted with AJHP's manuscript checklist. The text should be concise, and the number of references, tables, and figures should be limited.

Aged↗

PubMed2000

In vivo modulation of CYP enzymes by quinidine and rifampin.

BACKGROUND: The metabolism of drugs and other xenobiotics is mediated by enzymes whose activities can be modulated by different compounds. The activities of these modulators have the potential to be used to optimize drug action, prevent toxicity, or identify the enzymes involved in a reaction. This approach requires that selective agents be used for specific enzymes. However, selectivity of action has been poorly characterized in vivo. METHODS: This study investigated the effect of 3 and 28 days of treatment with quinidine (200 mg daily) and rifampin (INN, rifampicin) (600 mg daily) on the activities of four cytochrome P450 enzymes and N-acetyltransferase in 28 healthy young male volunteers divided into three groups with a cocktail of drug probes used, including caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and dapsone. RESULTS: Quinidine selectively and almost completely inhibited the activity of CYP2D6 from day 3 through day 28 without affecting any other enzymes. Rifampin showed evidence of time-dependent induction of the activities of all measured oxidative routes of metabolism but decreased the acetylation ratio in fast acetylators. The quinidine/rifampin combination resulted in selective CYP2D6 inhibition and induction of all other enzymes evaluated over this time period, suggesting that predictable complex interactions occur with the drug combination. CONCLUSIONS: These observations illustrate the value of simultaneous assessment of the effect of modulators on the activities of multiple specific enzymes with the drug cocktail approach.

Acetylation↗

PubMed2000

A pharmacokinetic study of amphotericin B lipid complex injection (Abelcet) in patients with definite or probable systemic fungal infections.

This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.

Adult↗

PubMed2000

Cigarette smoking, N-acetyltransferase 2 acetylation status, and bladder cancer risk: a case-series meta-analysis of a gene-environment interaction.

Tobacco use is an established cause of bladder cancer. The ability to detoxify aromatic amines, which are present in tobacco and are potent bladder carcinogens, is compromised in persons with the N-acetyltransferase 2 slow acetylation polymorphism. The relationship of cigarette smoking with bladder cancer risk therefore has been hypothesized to be stronger among slow acetylators. The few studies to formally explore such a possibility have produced inconsistent results, however. To assess this potential gene-environment interaction in as many bladder cancer studies as possible and to summarize results, we conducted a meta-analysis using data from 16 bladder cancer studies conducted in the general population (n = 1999 cases), Most had been conducted in European countries. Because control subjects were unavailable for a number of these studies, we used a case-series design, which can be used to assess multiplicative gene-environment interaction without inclusion of control subjects. A case-series interaction odds ratio (OR) > 1.0 indicates that the relationship of cigarette smoking and bladder cancer risk is stronger among slow acetylators as compared with rapid acetylators. We observed an interaction between smoking and N-acetyltransferase 2 slow acetylation (OR, 1.3; 95% confidence interval, 1.0-1.6) that was somewhat stronger when analyses were restricted to studies conducted in Europe (OR, 1.5; confidence interval, 1.1-1.9), a pooling that included nearly 80% of the collected data. Using the predominantly male European study population and assuming a 2.5-fold elevation in bladder cancer risk from smoking, we estimated that the population attributable risk percent was 35% for slow acetylators who had ever smoked and 13% for rapid acetylators who had ever smoked. These results suggest that the relationship of smoking and bladder cancer is stronger among slow acetylators than among rapid acetylators.

Acetylation↗

PubMed1999

Estrogen and tamoxifen metabolites protect smooth muscle cell membrane phospholipids against peroxidation and inhibit cell growth.

The goal of this study was to test the hypothesis that antioxidant estrogens, by a mechanism independent of the estrogen receptor, protect phospholipids residing in the plasma membrane of vascular smooth muscle cells from peroxidation and peroxidation-induced cell growth and migration. Peroxidation of membrane phospholipids was assessed by HPLC analysis of phospholipids extracted from rat aortic vascular smooth muscle cells prelabeled with cis-parinaric acid (a fatty acid that is susceptible to peroxidation, which quenches its fluorescent properties). Incubation of cells for 2 hours with the peroxyl radical donor 2,2'-azobis-2,4-dimethylvaleronitrile (AMVN) caused peroxidation of all measured membrane phospholipids. This effect was attenuated by pretreating cells for 15 minutes with 50 to 5000 ng/mL of 2-hydroxyestradiol (strong antioxidant but weak estrogen-receptor ligand) or 4-hydroxytamoxifen (strong antioxidant and potent estrogen-receptor ligand), but not by estrone or droloxifene (both weak antioxidants but potent estrogen-receptor ligands). Moreover, pretreatment of cells for 20 hours with physiological concentrations (0.3 ng/mL) of 2-hydroxyestradiol or pharmacologically relevant concentrations of 4-hydroxytamoxifen (40 ng/mL) also decreased AMVN-induced phospholipid peroxidation. Both 2-hydroxyestradiol and 4-hydroxytamoxifen were as effective as 2,2,5, 7,8-pentamethyl-6-hydrochromane (an antioxidant homolog of vitamin E) in attenuating AMVN-induced peroxidation of membrane phospholipids. Also, physiological concentrations of 2-hydroxyestradiol, but not estrone, and pharmacologically relevant concentrations of 4-hydroxytamoxifen attenuated AMVM-induced DNA synthesis, cell proliferation, and cell migration. These studies demonstrate in vascular smooth muscle cells that antioxidant estrogens via a non-estrogen receptor-dependent mechanism attenuate peroxidation of membrane phospholipids and peroxidation-induced cell growth and migration.

Animals↗

PubMed1999

Development of dapsone toxicity in patients with inflammatory dermatoses: activity of acetylation and hydroxylation of dapsone as risk factors.

BACKGROUND: Alternative independent routes of dapsone metabolism include N-hydroxylation to the hydroxylamine, a potentially toxic metabolite, by cytochrome P450 enzymes and acetylation to a nontoxic metabolite by N-acetyltransferase. Potentially, therefore, the relative extents of these two routes in an individual could determine the occurrence of adverse reaction with dapsone therapy. METHODS: Phenotypic activity of these two routes of metabolism was assessed in 18 patients receiving longterm dapsone therapy for inflammatory dermatoses and was related to the development of dapsone toxicity. N-Hydroxylation was assessed by the dapsone recovery ratio, a ratio of dapsone hydroxylamine to the sum of hydroxylamine and dapsone in 8-hour urine, whereas N-acetylation was assessed by the acetylation ratio, a ratio of monoacetyldapsone to dapsone in 8-hour plasma sample after an oral dose of dapsone. RESULTS: There was wide intersubject variation in both the acetylation ratio and the dapsone recovery ratio, but both phenotypic measures remained stable within individuals. The dapsone recovery ratio showed a tendency toward being lower in fast than in slow acetylators, but this was not statistically significant. There was an inverse relationship between acetylation and hydroxylation (r = -0.69; P < .005) at steady state that was not apparent after the first dose. Neurotoxicity developed in two subjects and hemolytic anemia developed in two subjects. Plasma levels of dapsone in these four subjects were similar to those in subjects who showed no toxicity. All four were slow acetylators and three were rapid hydroxylators, consistent with the toxic nature of dapsone hydroxylamine. CONCLUSIONS: These observations are consistent with what is known about the toxicity profile of dapsone metabolites and suggest that assessing N-acetylation and N-hydroxylation capacities can help to identify subjects at increased risk of a toxic response. This approach of assessing the phenotypic measures of drug-metabolizing activity to predict adverse reaction may also apply to other drugs with metabolic-based adverse effects.

Acetylation↗

PubMed1999

Effectiveness of antipsychotic therapy in a naturalistic setting: a comparison between risperidone, perphenazine, and haloperidol.

BACKGROUND: Therapeutic ineffectiveness and noncompliance with antipsychotic agents are major contributors to rehospitalization in patients with psychotic disorders. It is unknown whether risperidone's favorable side effect profile compared with that of the conventional antipsychotics results in improved compliance and reduced hospitalizations in a naturalistic setting. The purpose of this study was to test the hypothesis that treatment with risperidone reduces readmission rates and associated costs when compared with treatment with perphenazine or haloperidol. METHOD: Inpatients prescribed either risperidone, perphenazine, or haloperidol between January 1, 1995, and December 31, 1995, as a single oral antipsychotic at discharge were retrospectively identified. Data were collected for that index hospitalization and for a 1-year follow-up period. Primary outcome measures included re-admission rates, changes in antipsychotic therapy, anticholinergic drug use, and costs. RESULTS: There were 202 evaluable patients (81 treated with risperidone, 78 with perphenazine, and 43 with haloperidol). Baseline demographics were similar between groups except that more patients in the risperidone group had a primary diagnosis of psychotic disorder or had been hospitalized in the year prior to study. The percentage of patients readmitted during the 1-year follow-up period was similar among drug groups (41% risperidone, 26% perphenazine, and 35% haloperidol) when controlled for baseline differences in diagnosis and hospitalization history (p = .32). Anticholinergic drug use was more common in the haloperidol group (p = .004). Mean yearly cost (drug + hospitalization) in the risperidone group was $20,317, nearly double that in the other treatment groups (p < .001). CONCLUSION: The results from this naturalistic study indicate that the high cost of risperidone is not offset by a reduction in readmission rates when compared with conventional antipsychotics.

Adolescent↗

PubMed1998

Use of chlorzoxazone as an in vivo probe of cytochrome P450 2E1: choice of dose and phenotypic trait measure.

Chlorzoxazone is being developed and proposed for use as a probe to measure in vivo cytochrome P4502E1 activity, but the phenotypic trait measures that are used vary. Although the doses proposed for phenotyping range from 250 mg to 750 mg, the effect of dose on chlorzoxazone hydroxylation has not previously been evaluated. The purpose of this study was to characterize the pharmacokinetics of chlorzoxazone in normal healthy volunteers (N = 6) after single randomized oral doses of 250 mg and 750 mg. An additional 10 volunteers underwent a detailed pharmacokinetic study using the 250-mg dose to further evaluate proposed phenotypic trait measures (N = 16). Timed blood and urine samples were obtained for 10 hours for chlorzoxazone and 6-hydroxychlorzoxazone determination by HPLC. Pharmacokinetic parameter estimates were estimated using noncompartmental methods. Evaluation of phenotypic trait measures show that 6-hydroxychlorzoxazone to chlorzoxazone plasma concentration ratios at 2 to 4 hours after drug administration demonstrated the highest correlations with metabolite formation clearance (r = 0.9; P < 0.001). Urine-based parameters (e.g., total recovery) were not significantly related to formation clearance (r = 0.5; P > 0.05). Dose dependency in chlorzoxazone metabolism was shown by a 30% increase (P < 0.05) in the dose-normalized area under the concentration-time curve (AUC) of chlorzoxazone and lower incremental dose-normalized urinary recovery of 6-hydroxychlorzoxazone at early timepoints after the 750-mg dose. In addition, the plasma ratio of 6-hydroxychlorzoxazone to chlorzoxazone at 4 hours was reduced by 48% in 5 of 6 subjects after the 750-mg dose (P > 0.05). These data suggest that 6-hydroxylation was saturated at the higher dose and illustrate the importance of dose selection in phenotyping. The results of this study indicate that a chlorzoxazone dose of 250 mg should be used and that a single plasma ratio obtained 2 to 4 hours after dosing is reflective of chlorzoxazone 6-hydroxylation and thus may serve as a cytochrome P4502E1 phenotypic trait measure.

Adolescent↗

PubMed1998

Teaching clinical pharmacology and therapeutics: selective for fourth-year medical students.

Teaching clinical pharmacology remains both a lifelong learning process and a lifelong challenge for clinical pharmacologists and other medical educators. In the current information age, with an explosion of drug-related data, the prime topic for discussion is how to teach clinical pharmacology. This article describes our response to the challenges in developing a selective course in clinical pharmacology, and our experience from the first 2 years of the course. Our emphasis is on how to provide in an efficient way knowledge, skills, and attitudes students will need as physicians in the coming decades. Faculty from the Center for Clinical Pharmacology at the University of Pittsburgh in conjunction with faculty from the University of Pittsburgh School of Medicine have developed a one-month intensive course in clinical pharmacology. The integrated course program consists of four overlapping components: 1) general clinical pharmacology (focused on individualization of drug therapy); 2) rational prescribing principles (general principles of drug selection, how to prepare a personal formulary); 3) disease-specific clinical topics (pharmacotherapy of diseases and medical conditions most commonly seen in routine medical practice); and 4) workshops for special attention topics (pharmacokinetics, pain treatment, toxicology, dialysis). In congruence with established educational goals, the course includes drug-, patient-, and disease-oriented concepts. A variety of learning formats (didactic and interactive lectures, one-day problem-based learning sessions, small group case discussions, self-directed and small group directed learning, quizzes, and computer-assisted learning) are used to teach students how to apply the general concepts of clinical pharmacology and rational pharmacotherapy to clinical medicine, and to prepare them to become independent lifelong learners in therapeutics. Student feedback from the first 2 years of this course indicates that this multi-modal teaching format is effective. The majority of students who took the course in clinical pharmacology in 1997 found it to be very beneficial.

Curriculum↗

PubMed1998

All-trans-retinoic acid modulation of drug-metabolizing enzyme activities: investigation with selective metabolic drug probes.

PURPOSE: All-trans-retinoic acid (ATRA) is a retinoid analogue that has been shown to be effective in acute promyelocytic leukemia. It is currently being investigated for efficacy in the treatment and prevention of various types of cancer. One of the factors limiting its use is the observed increase in ATRA clearance and elimination which occurs shortly after treatment is started, leading to reduced levels of drug in the body and loss of effectiveness. ATRA efficacy may be enhanced if this autoinduction of metabolism can be overcome, for example through the inhibition of the activity of the induced specific metabolizing enzyme(s). This requires the identification of this induced enzyme(s) and development of approaches to selectively inhibit its activity. METHODS: In the course of a phase II evaluation of ATRA in prostate cancer, we investigated the activities of five specific cytochrome P450 (CYP) (CYPs 1A2, 2C19, 2D6, 2E1 and 3A4) and N-acetyltransferase enzymes using a newly developed five-drug cocktail involving caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone respectively. Enzyme activities were assessed in 17 patients with hormone-refractory prostate cancer before the initiation of ATRA therapy, after 14 days of continuous ATRA administration and 7 days after cessation of drug therapy. RESULTS: After 14 days of ATRA therapy, the activities of CYP2E1 (chlorzoxazone hydroxylase) and N-acetyltransferase (in fast acetylators only) were increased by 83% and 29% (P < 0.05), respectively. Both activities returned to baseline by 7 days after cessation of therapy and the profiles were similar to the changes seen in the clearance of ATRA itself. There were no changes in the activities of any of the other enzymes investigated. CONCLUSION: This study shows that ATRA selectively modulates the activities of specific metabolizing enzymes and that this approach may be useful in identifying enzymes that can be explored in an attempt to mitigate ATRA autoinduction through selective modulation of enzyme activities. Further investigations are required to determine whether the elevated enzymes are also responsible for the increased clearance and elimination of ATRA.

Adenocarcinoma↗

PubMed1998

Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6.

BACKGROUND AND OBJECTIVES: Drug metabolism is influenced by liver disease because of the central role that the liver plays in metabolic activities in the body. However, it is still unclear how activities of specific drug-metabolizing enzymes are influenced by the presence and severity of liver disease. As a consequence, alteration in metabolism of specific drugs cannot be easily predicted or appropriate dosage adjustment recommendations made. METHODS: The activities of cytochromes P450 (CYP) 2C19 and 2D6 were investigated in a group of patients with mild or moderate liver disease (n = 18) and a group of healthy control subjects (n = 10). The disposition of racemic mephenytoin for CYP2C19 and debrisoquin for CYP2D6 were characterized in plasma and urine samples collected over 192 hours. RESULTS: The elimination of S-mephenytoin was severely reduced among patients with liver disease, resulting in a 79% decrease in plasma clearance for all patients combined. This reduction was related to the severity of disease, patients with moderate disease being affected more severely than patients with mild disease. Similar differences were observed in the urinary excretion of 4'-hydroxymephenytoin metabolite. By contrast, there was no effect on the disposition of R-mephenytoin or debrisoquin. CONCLUSION: These results show selectivity in the effect of liver disease on activities of specific metabolizing enzymes, CYP2C19 being more sensitive than CYP2D6. They suggest that recommendations for modification in drug dosage in the presence of liver disease should be based on knowledge of the particular enzyme involved in metabolism of the drug. The results emphasize the need for further studies of each specific drug-metabolizing enzyme in the presence of liver disease.

Adult↗

PubMed1998

Drugs in liver disease.

Explore the source record for details and available documents.

Chemical and Drug Induced Liver Injury↗

PubMed1998

Induction of CYP2E1 activity in liver transplant patients as measured by chlorzoxazone 6-hydroxylation.

OBJECTIVE: To examine the phenotypic expression of CYP2E1 in liver transplant patients, as measured by the in vivo probe chlorzoxazone, and to evaluate CYP2E1 activity over time after transplantation. METHODS: Thirty-three stable liver transplant patients were given 250 mg chlorzoxazone within 1 year after transplantation as part of a multiprobe CYP cocktail; urine and blood were collected for 8 hours. Chlorzoxazone and 6-hydroxychlorzoxazone concentrations were determined by HPLC. Twenty-eight healthy control subjects, eight patients with moderate to severe liver disease, and four patients who had not received liver transplants were also studied for comparison. The chlorzoxazone metabolic ratio, calculated as the plasma concentration of 6-hydroxychlorzoxazone/chlorzoxazone at 4 hours after chlorzoxazone administration, was used as the phenotypic index. In a subgroup of patients and control subjects, additional blood samples were obtained to allow for the calculation of chlorzoxazone pharmacokinetic parameters by noncompartmental methods. RESULTS: The chlorzoxazone metabolic ratio for the liver transplant patients in the first month after transplantation (mean +/- SD, 6.4 +/- 5.1) was significantly higher than that after 1 month after surgery (2.1 +/- 2.0), when the chlorzoxazone metabolic ratio was not different from control subjects (0.8 +/- 0.5). The chlorzoxazone metabolic ratios in the patients who had not received liver transplants (1.1 +/- 0.7) were equivalent to those of healthy control subjects. The maximum observed 6-hydroxychlorzoxazone plasma concentration was 3046 +/- 1848 ng/ml in seven liver transplant patients in the first month after surgery compared with 1618 +/- 320 ng/ml in 16 healthy control subjects (p < 0.05). The maximum observed concentration of chlorzoxazone, the chlorzoxazone apparent oral clearance, and the formation clearance of 6-hydroxychlorzoxazone were also significantly different between the groups. CONCLUSIONS: We conclude that significant induction of CYP2E1, as indicated by the chlorzoxazone metabolic ratio, occurs in the first month after surgery in liver transplant patients and that drugs that are substrates for CYP2E1 may require dosage alteration during that period. Contrary to expectations, drug metabolism is not uniformly depressed after liver transplantation.

Adult↗

PubMed1998

Chloroquine modulation of specific metabolizing enzymes activities: investigation with selective five drug cocktail.

AIMS: The aim of this study was to investigate whether chloroquine can inhibit drug metabolism in humans, if such inhibition is general or selective for certain enzymes and evaluate the potential for and clinical significance of any drug-drug interactions when chloroquine is co-administered with other drugs. METHODS: The study was conducted in fourteen normal non-smoking healthy male volunteers using a cocktail of five drugs consisting of caffeine, mephenytoin, debrisoquine, chlorzoxazone and dapsone to assess activities of cytochromes P450 (CYP) 1A2, 2C19, 2D6, 2E1 and 3A4 respectively. Dapsone was also used to assess N-acetyltransferase activity. The activities were assessed at baseline, after one and seven daily doses (250 mg daily) of chloroquine and 7 and 14 days after stopping chloroquine dosing. RESULTS: Chloroquine caused a progressive and significant decrease in CYP2D6 activity as measured by debrisoquine metabolism from first to seventh dose and the activity returned to baseline gradually over 14 days after stopping administration. There was no effect on the metabolism of any of the other probe drugs. CONCLUSIONS: Chloroquine has been shown to be capable of inhibiting the activity of CYP2D6 in vivo in humans. This effect is selective as activities of other enzymes investigated were not affected. The effect was modest but suggests a potential for drug-drug interactions when co-administered with other drugs that are substrates for this enzyme. The clinical significance of such an interaction will depend on the therapeutic index of any drug involved.

Adult↗

PubMed1998

The cytochrome P450 suicide inhibitor, 1-aminobenzotriazole, sensitizes rats to zymosan-induced toxicity.

Reduction in whole body cytochrome P450 (CYP 450) activity is evident in humans who develop trauma and sepsis-induced multiple organ failure (MOF). It is not known whether this has any deleterious or protective effect. Intraperitoneal injection of zymosan, the cell wall of Saccharomycoses A, induces dose-dependent inflammation with concomitant MOF in rats. High dose intraperitoneal zymosan (100 mg/100 g body weight) causes mortality and organomegaly in rats; low dose zymosan (20 mg/100 g body weight) does not. To study a role for CYP 450 in zymosan-induced toxicity, we examined the effect of the non-specific CYP 450 suicide inhibitor 1-aminobenzotriazole (1-ABT)(80 mg/kg/d), on rats treated with low dose zymosan. The 90% reduction in CYP 450 content achieved by this dose of 1-ABT was associated with 58% mortality in rats treated with low dose zymosan, in contrast to no mortality in rats treated with low dose zymosan alone (p < 0.01). In survivors, liver and lung organomegaly (p < 0.01), and polymorphonuclear leukocyte accumulation in the liver (p < 0.01) were increased after zymosan administration in rats treated with 1-ABT compared to those without 1-ABT. There was no effect of treatment with 1-ABT on the increased urinary excretion of nitric oxide byproducts observed after zymosan administration. These observations are consistent with the hypothesis that the CYP 450 enzyme system is an endogenous protectant in this experimental model of inflammation-induced MOF.

Animals↗