Re: Doc visit results

Hello.

Re:
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Apxr - the Medscape links that you provided are inaccessible (don't you hate that?) A log-in is needed now. I've been able to read some of their abstracts/articles, but not today!
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Blast it! Now I can't access the info either. Medscape is annoying; must remember that.





Anyway, here's the excerpt that I intended to share:

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Introduction
Metronidazole is a substituted imidazole Antibiotic that is widely used to treat anaerobic bacterial, Helicobacter pylori, and protozoal infections. It is also commonly included in bowel-preparation regimens before colorectal surgery. Metronidazole is reported to have several clinically significant drug interactions due to the inhibition of oxidative drug metabolism. However, the effects of metronidazole on the activity of specific cytochrome P450 (CYP) isoforms has not been reported, and several of the reported drug interactions are based on single case reports.[1-4]

Although metronidazole appears to be an important inhibitor of CYP2C9 activity,[5-7] the evidence supporting inhibition of CYP3A activity in humans is weak.[1-4,7-10] Standard drug interaction textbooks and computer software programs routinely warn of an interaction between metronidazole and common CYP3A substrates, including cyclosporine and carbamazepine.[11,12] The clinical relevance of these interactions, especially with a short course of therapy administered preoperatively or in the treatment of Trichomonas vaginalis infections, is not clear.
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and also this small one:

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..Metronidazole does not affect the clearance of theophylline, a CYP1A2 substrate,[25,26] and contrary to several case reports,[1-4] controlled studies involving substrates for CYP3A4, such as midazolam,[10] alprazolam,[7] diazepam,[8] ethinyl estradiol,[9] and R-warfarin,[5] also indicate no important inhibition of metabolism due to metronidazole. The lack of effect seen in our study is consistent with the other controlled studies involving CYP3A4 substrates.

One potential explanation to resolve the apparent discrepancy between the controlled studies and case reports regarding the effect of metronidazole on metabolism of CYP3A substrates is that the case reports all included patients who were acutely ill.[1-4] The case reports may represent a drug-disease interaction, rather than a drug-drug interaction involving metronidazole...
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..which seems to suggest an 'apparent discrepancy' both in the results and/or in the understanding of certain interactions with Metronidazole -yes, Benzodiazepines included- when tested in the field. And those are the experts talking.






And here's the whole article from:
http://www.medscape.com/viewarticle/409792_print


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Effects of Metronidazole on Hepatic CYP3A4 Activity

Curtis E. Haas, Pharm.D., David C. Kaufman, M.D., and Robert C. DiCenzo, Pharm.D.

Pharmacotherapy 21(10):1192-1195, 2001. © 2001 Pharmacotherapy Publications
Abstract and Introduction
Abstract
Study Objective. To evaluate the effect of a short course of oral metronidazole, commonly used for bowel-preparation regimens, on hepatic cytochrome P450 (CYP) 3A4 activity, as measured by the [14C N-methyl]-erythromycin breath test (ERMBT) in healthy volunteers.

Design. Prospective, nonrandomized, interventional study.

Setting. University-affiliated, community, teaching hospital.

Subjects. Five healthy male volunteers.

Intervention. Subjects underwent a baseline ERMBT in the morning before receiving three oral doses of metronidazole 500 mg administered at 3 P.M., 7 P.M., and 11 P.M. Repeat ERMBTs were performed at 24, 72, and 96 hours after the initial ERMBT. Changes in ERMBT values were compared with baseline results using Freidman's repeated-measures analysis of variance on ranks.
Measurements and Main Results. The ERMBT values did not change significantly compared with baseline (p=0.82). Median (range) ERMBT values expressed as a percentage of baseline at 24, 72, and 96 hours were 110.3 (96.2-136.9), 101.3 (99.3-115.0), and 101.8 (95.5-116.3), respectively.
Conclusion. A short course of oral metronidazole does not result in a significant change in hepatic CYP3A4 activity as measured by the ERMBT.

Introduction
Metronidazole is a substituted imidazole Antibiotic that is widely used to treat anaerobic bacterial, Helicobacter pylori, and protozoal infections. It is also commonly included in bowel-preparation regimens before colorectal surgery. Metronidazole is reported to have several clinically significant drug interactions due to the inhibition of oxidative drug metabolism. However, the effects of metronidazole on the activity of specific cytochrome P450 (CYP) isoforms has not been reported, and several of the reported drug interactions are based on single case reports.[1-4]

Although metronidazole appears to be an important inhibitor of CYP2C9 activity,[5-7] the evidence supporting inhibition of CYP3A activity in humans is weak.[1-4,7-10] Standard drug interaction textbooks and computer software programs routinely warn of an interaction between metronidazole and common CYP3A substrates, including cyclosporine and carbamazepine.[11,12] The clinical relevance of these interactions, especially with a short course of therapy administered preoperatively or in the treatment of Trichomonas vaginalis infections, is not clear.

We recently completed a study evaluating the effects of major surgery on CYP3A4 activity. One of the patient cohorts underwent partial or complete colon resection and routinely received several doses of oral metronidazole the day before surgery. Since the effect of the oral metronidazole on preoperative hepatic CYP3A4 activity was unknown, we conducted a study with healthy volunteers to evaluate the effect of the preoperative metronidazole regimen on CYP3A4 activity, as measured by the [14C N-methyl]-erythromycin breath test (ERMBT).

Methods
Five healthy male volunteers aged 25-40 years participated in the study. These subjects had no known acute or chronic medical conditions and were not taking any prescription or over-the-counter drugs. All subjects were nonsmokers and refrained from alcohol consumption for at least 48 hours before and during the study. The study protocol was approved by the ViaHealth Clinical Investigations Committee and the Radiation Safety Committee. All subjects provided written informed consent.

On day 1 of the study, subjects underwent an ERMBT (Metabolic Solutions, Inc., Nashua, NH) between 8 A.M. and 9 A.M. The test was conducted according to the manufacturer's recommended procedures. In brief, a 3-µCi dose of [14C N-methyl]-erythromycin (< 0.05 mg) was injected over 1 minute into an antecubital or other prominent vein of the forearm. Twenty minutes after completion of the injection, a breath sample was collected, using the breath collection kit provided by the manufacturer. Later that day, metronidazole 500 mg (UDL, Rockford, IL) was taken orally at 3 P.M., 7 P.M., and 11 P.M.

Approximately 24, 72, and 96 hours after the first breath test, between 8 A.M. and 9 A.M., subjects had a repeat ERMBT, performed as described above. These times were chosen to be equivalent to the preoperative test and the 48-hour and 72-hour postoperative tests performed during the study of colorectal surgery patients. The ERMBTs were performed at approximately the same time each day to eliminate concern about variation in CYP3A4 activity throughout the day. To control for the possibility of a carryover effect from the previous dose, a breath sample was collected just before each of the three doses of [14C N-methyl]-erythromycin. Residual radioactivity from the previous 14C-erythromycin injection was measured and subtracted from the 20-minute postdose breath sample. A small amount of 14C-erythromycin remains in the body after 24 hours and is metabolized to CO2 (Wagner DA, personal communication, June 15, 2001).[13] After completion of the last ERMBT on day 5 of the study, the subjects' participation was ended.

Breath samples were shipped immediately to Metabolic Solutions, Inc., where 14CO2 content was measured by standardized procedures. Measurements were performed using a Tri-Carb 2100TR liquid scintillation counter (Packard Instrument Company, Inc., Meriden, CT). The accuracy and inter- and intra-run precision for high and low controls all had a percentage coefficient of variation below 0.5%. The percentage of the erythromycin dose demethylated in the first hour was calculated using a validated method.[14,15]

To account for interindividual variation in baseline CYP3A4 activity, the ERMBT results from days 2, 4, and 5 were converted to percentage of the baseline value for each subject. Changes in ERMBT results as percentage demethylated in the first hour and as a percentage of the baseline value were compared using a Friedman repeated-measures analysis of variance on ranks. The statistical tests were performed using SigmaStat version 2.03 (SPSS, Inc., San Rafael, CA).

Results
Median (range) ERMBT results expressed as a percentage of the dose demethylated in the first hour at baseline, 24, 72, and 96 hours were 1.84 (1.11-2.26), 1.96 (1.61-2.47), 1.79 (1.26-2.29), and 1.94 (1.13-2.26), respectively. Median (range)ERMBT values expressed as a percentage of baseline at 24, 72, and 96 hours were 110.3 (96.2-136.9), 101.3 (99.3-115.0), and 101.8 (95.5-116.3), respectively. Figure 1 shows the results for the five subjects. Regardless of how the data are presented, there was no significant change in the ERMBT results following the short course of oral metronidazole (p=0.82 for both analyses). The percentage change in baseline ERMBT was more variable at the 24-hour time point, due to two subjects having an apparent increase in hepatic CYP3A4 activity. These increases were comparable to intrasubject variability reported previously with the ERMBT.[16]

Figure 1. Erythromycin breath test (ERMBT) results for individual subjects (percentage of the erythromycin dose demethylated in the first hour).

Discussion
The activity of hepatic CYP3A4 isoenzyme was estimated by the ERMBT, which uses a trace dose of intravenous [14C-N-methyl]-erythromycin. The N-demethylation of erythromycin is catalyzed by CYP3A4, and the appearance rate of 14CO2 in the breath has been correlated with hepatic CYP3A4 content.[17,18] In addition, ERMBT results correlate with the clearance of known CYP3A4 substrates,[14,19,20] increase with the administration of known inducers,[16] and decrease after administration of known inhibitors.[16,21-24] We chose the ERMBT for our studies since it is minimally invasive, well tolerated, and can be easily performed on many occasions to detect serial changes in activity over a short time.

Data on the effects of metronidazole on specific pathways of drug metabolism are limited. Available evidence suggests that metronidazole may inhibit metabolism of the CYP2C9 substrates S-warfarin[5] and phenytoin,[7] although the results with phenytoin have not been consistent.[8] Metronidazole does not affect the clearance of theophylline, a CYP1A2 substrate,[25,26] and contrary to several case reports,[1-4] controlled studies involving substrates for CYP3A4, such as midazolam,[10] alprazolam,[7] diazepam,[8] ethinyl estradiol,[9] and R-warfarin,[5] also indicate no important inhibition of metabolism due to metronidazole. The lack of effect seen in our study is consistent with the other controlled studies involving CYP3A4 substrates.

One potential explanation to resolve the apparent discrepancy between the controlled studies and case reports regarding the effect of metronidazole on metabolism of CYP3A substrates is that the case reports all included patients who were acutely ill.[1-4] The case reports may represent a drug-disease interaction, rather than a drug-drug interaction involving metronidazole. It is increasingly well appreciated that acute illness and the associated acute inflammatory response can result in a downregulation of drug metabolism by CYP enzymes; this is often referred to as a drug-cytokine interaction.[27,28]

It is also possible that metronidazole inhibits intestinal CYP3A4 to a much greater extent than hepatic CYP3A4, possibly due to high concentrations of metronidazole in the lumen of the intestine. Intestinal CYP3A4 inhibition leading to increased oral bioavailability could explain the case reports of drug interactions involving cyclosporine,[1,4] tacrolimus,[4] and quinidine.[3] However, one study reported that metronidazole had no effect on the pharmaco-kinetics of midazolam or 1¢-hydroxymidazolam, or on the ratio of midazolam:1¢-hydroxymidazolam after oral administration of midazolam.[10] This report argues against an effect of metronidazole on intestinal CYP3A4 activity.

P-glycoprotein (P-gp) is a transmembrane glycoprotein that acts as a drug efflux pump across epithelial cell membranes of many organs, including the intestinal wall.[29,30] Cyclosporine, tacrolimus, and quinidine,[30] but not midazolam,[31] are P-gp substrates. If metronidazole inhibits P-gp activity within the intestinal epithelium, the absorption and oral bioavailability of P-gp substrates might be increased, while there would be no expected effect on the absorption of oral midazolam. It is unknown whether metronidazole affects P-gp activity.

In this study, a short course of oral metron-idazole, commonly used for bowel-preparation regimens, did not result in a significant change in CYP3A4 activity as measured by the ERMBT. Since the single 2-g oral dose commonly used to treat vaginitis secondary to Trichomonas vaginalis represents a similar dose and duration of exposure, we anticipate a lack of interaction with this regimen. These results do not exclude the possibility of a significant effect of metronidazole on CYP3A4 activity at a higher dose or a longer duration of treatment. This study involved healthy volunteers, and it is possible that a drug interaction may be more apparent in acutely ill patients.

Another limitation of this study is its small sample size, which may have led to a type II error. We measured 15 ERMBT results after baseline measurements in five subjects. The average baseline value was 1.75%/hour, with an average difference from baseline of 0.38%/hour on repeated measures. The standard deviation of the average change from baseline was 0.09%/hour. Clinically important inhibitors of hepatic CYP3A4, including ketoconazole,[22, 23] clarithromycin,[25] amprenavir,[23,24] and delavirdine,[21] have been reported to decrease baseline ERMBT results by 65-85%. We assume that a 40% decrease of ERMBT from baseline is the smallest clinically important change in CYP3A4 activity to detect. The probability that the true change in ERMBT was as high as 40% in our study is considerably less than 0.01. Based on these estimates, it is unlikely that our limited sample size resulted in a type II error that failed to detect a clinically important change in hepatic CYP3A4 activity.

Drug-interaction screening software programs routinely warn of drug interactions between metronidazole and CYP3A substrates. However, our results indicate that these warnings are not clinically relevant for the preoperative patient receiving metronidazole as part of a bowel-preparation regimen. Since metronidazole is a common drug, further investigation into its effects on the activity of specific CYP isoenzyme pathways, P-gp activity, and clinically important substrates is indicated.

References

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Authors from: the Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York (Drs. Haas and DiCenzo); and the Department of Surgery, University of Rochester Medical Center, Rochester, New York (Dr. Kaufman).
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