Phenotyping of drug-metabolizing enzymes in adults: a review of in-vivo cytochrome P450 phenotyping probes.

Cytochrome P450 phenotyping provides valuable information about real-time activity of these important drug-metabolizing enzymes through the use of specific probe drugs. Despite more than 20 years of research, few conclusions regarding optimal phenotyping methods have been reached. Caffeine offers many advantages for CYP1A2 phenotyping, but the widely used caffeine urinary metabolic ratios may not be the optimal method of measuring CYP1A2 activity. Several probes of CYP2C9 activity have been suggested, but little information exists regarding their use, largely due to the narrow therapeutic index of most CYP2C9 probes. Mephenytoin has long been considered the standard CYP2C19 phenotyping probe, but problems such as sample stability and adverse effects have prompted the investigation of potential alternatives, such as omeprazole. Several well-validated CYP2D6 probes are available, including dextromethorphan, debrisoquin and sparteine, but, in most cases, dextromethorphan may be preferred due to its wide safety margin and availability. Chlorzoxazone remains the only CYP2E1 probe that has received much study. However, questions concerning phenotyping method and involvement of other enzymes have impaired its acceptance as a suitable CYP2E1 phenotyping probe. CYP3A phenotyping has been the subject of numerous investigations, reviews and commentaries. Nevertheless, much controversy regarding the selection of an ideal CYP3A probe remains. Of all the proposed methods, midazolam plasma clearance and the erythromycin breath test have been the most rigorously studied and appear to be the most reliable of the available methods. Despite the limitations of many currently available probes, with continued research, phenotyping will become an even more valuable research and clinical resource.

Use of midazolam urinary metabolic ratios for cytochrome P450 3A (CYP3A) phenotyping.

Midazolam (MDZ) total clearance (ClT) is widely used for cytochrome P450 3A (CYP3A) phenotyping, but requires up to eight blood samples. This study was conducted to compare the use of midazolam ClT to use of a midazolam urinary metabolic ratio for CYP3A phenotyping. Ten male and 10 female subjects received i.v. midazolam 0.025 mg/kg eight times over a 4-month period at approximately 2-week intervals. The first six phenotyping measures were used to estimate baseline CYP3A activity, then subjects received the moderate CYP3A inhibitor fluvoxamine 150 mg/day for the last 4 weeks (two phenotyping visits) of the study. Serial blood samples were obtained for calculation of ClT. Urine was collected for 6 h following each midazolam dose. Midazolam, 1'-hydroxymidazolam (1-OHMDZ), and 4-hydroxymidazolam were measured in plasma and urine by liquid chromatography with tandem mass spectrometry (LC/MS/MS). Analysis of 148 samples from 20 subjects revealed a weak overall correlation between the urinary ratio of 1-OHMDZ/MDZ to midazolam ClT of r(s) = 0.372 (P = 0.0001). There was no correlation when examining either baseline samples or fluvoxamine-inhibited samples alone (r(s) = 0.101, P = 0.289 and r(s) = 0.266, P = 0.123, respectively). The median (range) urinary ratio decreased significantly with fluvoxamine [219 (141-409) versus 127 (50-464); P = 0.005] and to a similar extent to the midazolam ClT (-33.6% versus -42.4%, respectively; P > 0.05). Median urinary recovery of the i.v. midazolam dose varied between 1.4% and 53% and was significantly lower in samples collected while patients were receiving fluvoxamine (34.3% versus 23.1%; P= 0.0004). Based on these results, although this midazolam urinary ratio was not very reflective of baseline CYP3A activity, it may be a useful indicator of CYP3A inhibition.

Dose dependency of dextromethorphan for cytochrome P450 2D6 (CYP2D6) phenotyping.

Most dextromethorphan CYP2D6 phenotyping studies use a 30-mg dose, but data that show superiority of any particular dose are lacking. We compared metabolic ratios from six different dextromethorphan phenotyping doses to ascertain whether linearity existed over a dosage range. Forty subjects were enrolled in the study. Each subject received 0.05 mg/kg, 0.15 mg/kg, 0.3 mg/kg, 30 mg, 0.8 mg/kg, and 1.2 mg/kg dextromethorphan in a randomized crossover fashion. Urinary dextromethorphan to dextrorphan molar ratios were used to measure CYP2D6 activity. Single blood samples were obtained for CYP2D6 genotyping, which revealed one poor metabolizer and 39 extensive metabolizers. A statistical difference was found for the molar ratio between the 0.8 mg/kg and the 1.2 mg/kg dose compared with the other four doses. None of the 39 genotypic extensive metabolizers were incorrectly phenotyped with any of these doses. These data support the use of moderate doses of dextromethorphan for phenotyping to avoid dose dependency.

Combined phenotypic assessment of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase with the "Cooperstown cocktail".

BACKGROUND: Simultaneous administration of several probes enhances the utility of phenotyping, but poor specificity, side effects, and use of drugs not approved by the Food and Drug Administration limit the usefulness of prior phenotyping cocktails. OBJECTIVES: To evaluate potential drug-drug interactions associated with use of a cocktail of caffeine, omeprazole, dextromethorphan, and midazolam for simultaneous phenotyping of CYP1A2, CYP2C19, CYP2D6, CYP3A, N-acetyltransferase-2, and xanthine oxidase. METHODS: Twelve subjects received caffeine + dextromethorphan, omeprazole, and midazolam (each alone), and a cocktail of caffeine + dextromethorphan + omeprazole + midazolam. Blood samples were collected at 120 minutes for omeprazole and 5/-hydroxyomeprazole, and at 0, 5, 30, 60, 120, 240, 300, and 360 minutes for midazolam. Twelve-hour urine samples were collected for analysis of dextromethorphan, caffeine, and metabolites. RESULTS: The median CYP1A2 metabolic ratio after administration of caffeine + dextromethorphan was not significantly different from that obtained with the cocktail (P = .84). Likewise, the median N-acetyltransferase-2, xanthine oxidase, and CYP2D6 metabolic ratios were not significantly different after cocktail administration (P = .977 for each N-acetyltransferase-2; P = .795 for xanthine oxidase; P = .75 for CYP2D6). The median CYP2C19 metabolic ratio after cocktail administration was not significantly different from that obtained after omeprazole administered alone (P = 1.000). Also, midazolam plasma clearance was not significantly different after cocktail administration compared with that after administration of midazolam alone (P = .708). The only side effect was sedation, which was associated with intravenous midazolam and occurred to a similar extent after both individual and cocktail phenotyping. CONCLUSIONS: These results indicate no pharmacokinetic or pharmacodynamic interactions that would limit the utility of this phenotyping cocktail for simultaneous measurement of the activity of multiple drug-metabolizing enzymes.

Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs.

STUDY OBJECTIVE: To examine the impact of individualized pharmacokinetic monitoring (IPM) on the development of aminoglycoside-associated nephrotoxicity (AAN). DESIGN: Retrospective case-control study. SETTING: Two teaching hospitals. SUBJECTS: Two thousand four hundred five patients who received aminoglycosides. INTERVENTION: Aminoglycoside therapy dosed by either IPM or physicians' directions. MEASUREMENTS AND MAIN RESULTS: Patients receiving IPM were significantly less likely to develop AAN by both univariate (7.9% vs 13.2%, p=0.02) and multivariate methods (odds ratio 0.42, p=0.002). Female sex was protective against AAN. Age 50 years and above, high initial aminoglycoside trough, long duration of therapy, and concurrent piperacillin, clindamycin, or vancomycin increased risk of AAN. We estimated that IPM decreased AAN costs by $90,995/100 patients. CONCLUSION: Individualized pharmacokinetic monitoring significantly decreased the frequency of AAN and its associated economic costs.

Metabolic basis of drug interactions in the intensive care unit.

Drug interactions are a potentially hazardous consequence of drug therapy, particularly in the critically ill. Many drug interactions result from changes in drug metabolism. These interactions can result in either an increase in toxicity or a decrease in effect. The process of normal drug metabolism depends on the activity of individual metabolizing enzymes. The activity of these enzymes can be altered by many factors, and it is alterations in these enzymes that account for most drug interactions. This article reviews normal and abnormal drug metabolism and discusses how this knowledge can be used to predict and prevent potential drug interactions.

Azathioprine hypersensitivity reaction in a patient with ulcerative colitis.

OBJECTIVE: To describe a case of azathioprine hypersensitivity in a patient with ulcerative colitis. CASE SUMMARY: A 40-year-old white man with ulcerative colitis, treated with chronic mesalamine and occasional steroids, was admitted to the hospital with a 3-day history of fever, nausea, vomiting, and a rash. Fourteen days prior to admission, the patient had been started on azathioprine for ulcerative colitis. Upon admission, azathioprine therapy was temporarily withheld, resulting in resolution of his signs and symptoms. Symptoms returned when azathioprine was restarted. It was decided that these signs and symptoms were most likely caused by azathioprine hypersensitivity, and the agent was discontinued. DISCUSSION: To our knowledge, this is the first reported case of azathioprine hypersensitivity in a patient with ulcerative colitis. The time course and presenting signs and symptoms support the diagnosis of azathioprine hypersensitivity, as does the patient's response to rechallenge. The mechanism of this hypersensitivity reaction is unclear, but may involve the nitroimidazole portion of the azathioprine molecule. CONCLUSIONS: Azathioprine hypersensitivity often presents with signs and symptoms resembling a systemic infection such as fever, leukocytosis, and evidence of end organ dysfunction. The diagnosis of azathioprine hypersensitivity should be considered in patients who have recently either initiated or increased their dosage of azathioprine.

Medication bezoars: a literature review and report of a case.

OBJECTIVE: To describe a case of a medication bezoar and to review the clinical presentation, diagnosis, risk factors, pathogenesis, complications, and treatment of medication bezoars. DATA SOURCES AND STUDY SELECTION: A MEDLINE search (January 1966-December 1997) of the English-language literature pertaining to bezoars was performed. These articles were scanned, and literature specifically discussing medication bezoars was selected. Additionally, the reference sections of pertinent review and case reports were scanned for additional relevant literature. DATA SYNTHESIS: Bezoars are concretions of foreign material within the body. In the case of medication bezoars, these concretions occur within the digestive tract and are composed of medications and/or medication vehicles. Rarely, however, is bezoar formation solely due to a medication. In nearly all reported cases the patient had one or more significant risk factors that contributed to bezoar formation. The exact method by which medications bezoars form is dependent on the particular type or combination of medications involved. Bezoar formation may be associated with significant complications for the patient due to the presence of the bezoar and because of the effects of the medication within the bezoar. Treatment of medication bezoars depends largely on the location and the cause of the bezoar. CONCLUSIONS: Medication bezoars are a rare but potentially serious complication of medication use in certain patients. These patients often present with signs and symptoms consistent with an obstruction of the gastrointestinal tract and represent an even greater diagnostic challenge due to the rarity of this complication. These patients also face significant complications from both the bezoar and the medication within the bezoar. To date, treatment of medication bezoars involves mainly physical manipulation of the bezoar through lavage, endoscopic removal, or, in most cases, surgical removal.