Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review.

Exogenous cannabinoids are structurally and pharmacologically diverse compounds that are widely used. The purpose of this systematic review is to summarize the data characterizing the potential for these compounds to act as substrates, inhibitors, or inducers of human drug metabolizing enzymes, with the aim of clarifying the significance of these properties in clinical care and drug interactions. In vitro data were identified that characterize cytochrome P-450 (CYP-450) enzymes as potential significant contributors to the primary metabolism of several exogenous cannabinoids: tetrahydrocannabinol (THC; CYPs 2C9, 3A4); cannabidiol (CBD; CYPs 2C19, 3A4); cannabinol (CBN; CYPs 2C9, 3A4); JWH-018 (CYPs 1A2, 2C9); and AM2201 (CYPs 1A2, 2C9). CYP-450 enzymes may also contribute to the secondary metabolism of THC, and UDP-glucuronosyltransferases have been identified as capable of catalyzing both primary (CBD, CBN) and secondary (THC, JWH-018, JWH-073) cannabinoid metabolism. Clinical pharmacogenetic data further support CYP2C9 as a significant contributor to THC metabolism, and a pharmacokinetic interaction study using ketoconazole with oromucosal cannabis extract further supports CYP3A4 as a significant metabolic pathway for THC and CBD. However, the absence of interaction between CBD from oromucosal cannabis extract with omeprazole suggests a less significant role of CYP2C19 in CBD metabolism. Studies of THC, CBD, and CBN inhibition and induction of major human CYP-450 isoforms generally reflect a low risk of clinically significant drug interactions with most use, but specific human data are lacking. Smoked cannabis herb (marijuana) likely induces CYP1A2 mediated theophylline metabolism, although the role of cannabinoids specifically in eliciting this effect is questionable.

Interpretation of Cytochrome P-450 Inhibition and Induction Effects From Clinical Data: Current Standards and Recommendations for Implementation.

Agents that modify cytochrome P-450 (CYP) enzyme activity are characterized as strong, moderate, or weak inhibitors or inducers based on the magnitude of their impact on substrate exposure in clinical studies. Criteria for these classifications are simple and semiquantitative. However, assignment of a given agent to a CYP inhibitor or inducer category is often complicated by limitations of the published data, inconsistent study findings, and other factors. CYP inhibitor and inducer categories are commonly used as a basis for differentiating drug interaction management recommendations. For example, product labeling for a CYP substrate may recommend avoidance in combination with strong inhibitors and dose reduction in combination with moderate inhibitors. When such recommendations exist, ambiguity or variability in placement of inhibitors or inducers into categories can introduce potentially harmful variations in clinical drug interaction management. Failure to adequately reflect the drug interaction potential of an agent by under-categorizing it (e.g., calling it weak when data point to moderate effects), for example, may lead clinicians to respond inadequately to real risks, or to ignore potential interactions altogether. Over-categorization may lead to actions such as over-adjustment of substrate doses or unnecessary avoidance of optimal treatments. This review describes the current criteria for assignment of CYP inhibitor and inducer categories, summarizes common circumstances leading to ambiguous or variable CYP inhibitor and inducer categorizations, and proposes an approach to data interpretation and application of current criteria under uncertainty. When applied to > 1,000 CYP reviews, the approach described has identified a clear categorization in almost all cases.

Finasteride treatment of hair loss in women.

OBJECTIVE: To review available evidence on the safety and efficacy of finasteride in the treatment of alopecia in women. DATA SOURCES: A literature search was conducted through PubMed (1948-March 2010) and MEDLINE (1950-March 2010) using the search terms finasteride and alopecia. References cited in relevant publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: All data sources identified were reviewed for inclusion. Reports of finasteride treatment of female alopecia were included in the review. This included prospective and retrospective trials, case series, and case reports. Studies in men were not included. DATA SYNTHESIS: Few pharmacologic options exist for women with alopecia who do not achieve satisfactory responses to topical minoxidil solution. Treatment successes with finasteride in women with female pattern hair loss, although an off-label indication, have been primarily described in uncontrolled studies and anecdotal reports. In 2 controlled clinical studies, finasteride showed no benefit over placebo or no treatment in female pattern hair loss. A finasteride regimen of 1 mg orally daily, as indicated in male pattern hair loss, may be recommended for those who fail or cannot tolerate minoxidil therapy. A 12-month trial is needed to assess stabilization of hair loss, and hair regrowth may take 2 years or longer. Although data are sparse, menopausal status, circulating androgen concentrations, and concomitant symptoms of hyperandrogenism do not appear to predict response to finasteride. Overall, finasteride is well tolerated; however, women of childbearing potential must adhere to reliable contraception while receiving finasteride, and treatment is contraindicated in pregnancy, due to known teratogenicity. CONCLUSIONS: Although objective evidence of efficacy is limited, finasteride may be considered for treatment of female pattern hair loss in patients who fail topical minoxidil treatment.

Impact of an Intravenous Magnesium Shortage on Potassium Doses in Adult Surgical Patients Receiving Parenteral Nutrition.

BACKGROUND: Shortages of parenteral nutrition (PN) components have been common in recent years. Effects on patient management and outcomes have not been well documented. This study aimed to determine the effect of a parenteral magnesium shortage, and an institutional decision to omit magnesium from adult PN, on magnesium and potassium doses and serum concentrations. MATERIALS AND METHODS: This was a retrospective cohort study of adult surgical patients during two 6-month periods: prior to the magnesium shortage (2011) and during the shortage (2012). The relation between study period and electrolyte doses was evaluated by unadjusted and adjusted mixed models, while the relation between study period and hypokalemia and hypomagnesemia exposure was evaluated by Student's t tests and multiple linear regression. RESULTS: During the shortage, patients received more supplemental magnesium (0.11-0.12 mEq/kg/d, P < .0001) but received less total daily magnesium (0.08-0.09 mEq/kg/d, P < .0001) and had greater exposure to hypomagnesemia (9.6-14.2 h·mcg/dL/h, P < .05 for all comparisons except multivariate analysis in a matched subpopulation). Patients received similar amounts of potassium in PN (0.06-0.08 mEq/kg/d less, P < .05 for full cohort but P > .05 for matched cohort), in supplemental doses (0.01-0.05 mEq/kg/d less, P > .05), and in total (0.07-0.14 mEq/kg/d less, P > .05), and they had similar exposure to hypokalemia. CONCLUSION: Daily magnesium doses were lower and hypomagnesemia exposure was greater during the shortage, but the differences were numerically small and their clinical significance was questionable. Potassium doses and hypokalemia exposure were not higher during the shortage. This supports the strategy of omitting magnesium from PN of select patients and supplementing as clinically necessary.

The effects of an informational video on patient knowledge, satisfaction and compliance with venous thromboembolism prophylaxis: a pilot study.

OBJECTIVE: Venous thromboembolism (VTE) is the leading cause of preventable death in hospitalized patients. Educational videos have been effectively used to increase patient satisfaction and knowledge. This study examined possible benefits of an educational video about VTE. METHODS: Medical patients receiving VTE prophylaxis were screened within 48 h of admission. Upon enrollment, patients were randomly assigned to either watch a 5 min educational video on VTE or not, in addition to standard VTE education. Within 24-48 h after randomization, all patients completed a survey assessing VTE prophylaxis knowledge and satisfaction. RESULTS: Patients who watched the video averaged 83% correct responses to knowledge-based questions (regarding VTE risk, symptoms, and preventative measures) versus an average score of 62% for patients in the no video group (p<0.001). Patients who watched the video were more satisfied with their VTE education (4.8 vs. 3.4 out of 5, p<0.001). CONCLUSION: This educational video effectively provided baseline information to patients about VTE and improved patient satisfaction. PRACTICE IMPLICATIONS: A VTE educational video can be an effective tool for improving patient knowledge of the condition.

Influence of metoprolol dosage release formulation on the pharmacokinetic drug interaction with paroxetine.

Studies have demonstrated an influence of dosage release formulations on drug interactions and enantiomeric plasma concentrations. Metoprolol is a commonly used beta-adrenergic antagonist metabolized by CYP2D6. The CYP2D6 inhibitor paroxetine has previously been shown to interact with metoprolol tartrate. This open-label, randomized, 4-phase crossover study assessed the potential differential effects of paroxetine on stereoselective pharmacokinetics of immediate-release (IR) tartrate and extended-release (ER) succinate metoprolol formulations. Ten healthy participants received metoprolol IR (50 mg) and ER (100 mg) with and without paroxetine coadministration. Blood samples were collected over 24 hours for determination of metoprolol plasma enantiomer concentrations. Paroxetine coadministration significantly increased S and R metoprolol area under the plasma concentration-time curve from time 0 to the 24-hour blood draw (AUC(0-24h)) by 4- and 5-fold, respectively for IR, and 3- and 4-fold, respectively, for ER. S/R AUC ratios significantly decreased. These results demonstrate a pharmacokinetic interaction between paroxetine and both formulations of metoprolol. The interaction is greater with R metoprolol, and stereoselective metabolism is lost. This could theoretically result in greater beta-blockade and lost cardioselectivity. The magnitude of the interaction was similar between metoprolol formulations, which may be attributable to low doses/drug input rates employed.

The impact of paroxetine coadministration on stereospecific carvedilol pharmacokinetics.

STUDY OBJECTIVE: to assess the impact of paroxetine coadministration on the stereoselective pharmacokinetic (PK) properties of carvedilol. DESIGN: prospective, randomized, 2-phase crossover. SETTING: the University of Michigan General Clinical Research Unit and Michigan Clinical Research Unit. PARTICIPANTS: twelve healthy volunteers aged 18 to 45 years, male and female, receiving no treatment with prescription or nonprescription medications. INTERVENTIONS: participants received single dose oral carvedilol (12.5 mg) with and without coadministration of immediate-release paroxetine (10 mg orally twice daily), in random order. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12, and 24 hours post-carvedilol dose for determination of R and S carvedilol plasma enantiomer concentrations by high pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: pharmacokinetic (PK) parameters were calculated for each enantiomer by noncompartmental methods and compared between study phases by analysis of variance (ANOVA) controlling for study phase order and subject, with Tukey's studentized range test post hoc. Area under the concentration-time curve (AUC) increased significantly with paroxetine coadministration, approximately 2.5-fold and 1.9-fold for the R and S enantiomers, respectively. R/S AUC ratio increased significantly, from approximately 2.3 to 3.0. Individual increases in enantiomeric AUCs with paroxetine coadministration ranged from 0% to 571% and changes in R/S ratio ranged from -8% to 108%. Heart rate, P-R interval, and blood pressure were monitored and no clinically significant changes in carvedilol effects were noted. CONCLUSION: this study demonstrated a PK drug-drug interaction between paroxetine and carvedilol, with considerable interparticipant variability in carvedilol PK parameters and magnitude of drug interaction. Stereoselectivity of carvedilol metabolism is preserved with paroxetine coadministration, and R/S AUC ratio generally widens. Although this drug interaction could potentially increase adrenergic antagonism and have significant clinical effects in patients, these effects were not seen in our healthy volunteer participants.