Optimizing screening and management of cardiovascular health in prostate cancer: A review.

In clinical practice, cancer management does not consistently encompass screening and identification of cardiovascular (CV) risk. The use of androgen deprivation therapy (ADT) in prostate cancer has been associated with increased CV risk and development of metabolic syndrome, necessitating identification of patients at risk in this population (e.g., those with pre-existing CV disease). A multidisciplinary team of Canadian physicians was assembled to develop a series of recommendations intended to identify patients who may benefit from optimal management of their CV disease and/or modification of cardiac risk factors. A key goal was the development of a simple screening tool for identification of patients with pre-existing CV disease. This simple and inclusive set of recommendations are intended for use within urology clinics to facilitate holistic approaches and simplify the management of patients.

Coffee inhibition of CYP3A4 in vitro was not translated to a grapefruit-like pharmacokinetic interaction clinically.

Grapefruit can augment oral medication bioavailability through irreversible (mechanism-based) inhibition of intestinal CYP3A4. Supplementary data from our recent coffee-drug interaction clinical study showed some subjects had higher area under the plasma drug concentration - time curve (AUC) and plasma peak drug concentration (Cmax) of the CYP3A4 probe felodipine compared to aqueous control. It was hypothesized that coffee might interact like grapefruit in responsive individuals. Beans from six geographical locations were consistently brewed into coffee that was separated chromatographically to a methanolic fraction for in vitro inhibition testing of CYP3A4 metabolism of felodipine at 1% coffee strength. The effect of simultaneous incubation and 10-min preincubation with coffee fractions determined whether coffee had direct and mechanism-based inhibitory activity. A subsequent five-way randomized balanced controlled crossover clinical study evaluated the clinical pharmacokinetic interaction with single-dose felodipine. Grapefruit juice, water, or three of the in vitro tested coffees were ingested at 300 mL alone 1 h before and then with felodipine. In vitro, all six coffees decreased felodipine metabolism for both simultaneous and preincubation exposure compared to corresponding control. Five coffees demonstrated mechanism-based inhibition. Grapefruit increased felodipine AUC0-8 (25 vs. 13 ng.h/mL, P < 0.001) and Cmax (5.8 vs. 2.7 ng/mL, P < 0.001) and decreased dehydrofelodipine/felodipine AUC0-8 ratio (0.84 vs. 1.29, P < 0.001), while the three coffees caused no change in these parameters compared to water. Despite high in vitro potency of CYP3A4 inhibition, the coffees did not cause a clinical pharmacokinetic interaction possibly from insufficient amount of inhibitor(s) in coffee reaching intestinal CYP3A4 during the absorption phase of felodipine. The results of this study highlight the need for follow-up clinical testing when in vitro results indicate the possibility of an interaction.

Coffee-Antihypertensive Drug Interaction: A Hemodynamic and Pharmacokinetic Study With Felodipine.

OBJECTIVES: A period of abstinence from coffee to permit caffeine elimination appears to enable increased blood pressure on subsequent exposure. We hypothesized that this would offset the antihypertensive effect of the dihydropyridine calcium channel blocker felodipine. METHODS: A randomized, single-dose, crossover study assessed hemodynamic and pharmacokinetic effects following 2 days without coffee and caffeine-containing foods. Consistently brewed black coffee (2×300ml), felodipine maximum recommended dose (10mg), and coffee plus felodipine were tested in middle-aged normotensive subjects. RESULTS: Pretreatment plasma caffeine concentrations were unquantifiable. After coffee, blood pressure changes (mm Hg) averaged over study hours 1-4 were increased for brachial systolic (7.6, P < 0.001) and diastolic (4.9, P < 0.001) and aortic systolic (7.4, P < 0.001), pulse (3.0, P < 0.05) and augmentation (1.4, P < 0.05) relative to baseline. After coffee plus felodipine, they were higher for brachial systolic (4.0, P < 0.05) and diastolic (3.9, P < 0.001) and aortic systolic (4.6, P < 0.05) compared to felodipine alone. The pressor effects of coffee and its modulation by felodipine were variable among individuals. Coffee containing caffeine (127mg) caused maximum pressor effect. Caffeine and felodipine pharmacokinetics were similar for coffee and felodipine given alone or in combination indicating an interaction having a pharmacodynamic basis. Plasma felodipine concentration-diastolic blood pressure reduction relationship shifted with coffee such that doubling the felodipine concentration would eliminate the pressor effect. However, this may increase the risk of adverse drug events particularly during the timeframe without coffee. CONCLUSION: Intermittent coffee ingestion might complicate hypertension diagnosis and management for many individuals.

Relative bioavailability and antioxidant potential of two coenzyme q10 preparations.

Coenzyme Q10 (CoQ10) is synthesized by the human body and found in certain foods. Daily supplementation of CoQ10 could protect against heart disease but the bioavailability of CoQ10 supplements depends on the formulation taken. We compared the bioavailability and antioxidant properties of two commercial CoQ10 formulations, a commercial grade CoQ10 powder (commercial grade CoQ) and a new BT-CoQ10 BIO-TRANSFORMED (BT-CoQ10) obtained by fermentation of a soy-based, CoQ10-rich media with baker's yeast. Eleven healthy individuals participated in a randomized two-way crossover trial, with a 3-week washout period. Capsules containing 300 mg of either BT-CoQ10 or commercial grade CoQ10 were given daily for 1 week and multiple blood samples were taken for CoQ10, glutathione and glutathione peroxidase (GPx) determination. In 3 subjects, baseline plasma CoQ10 levels were lower prior to BT than prior to commercial grade CoQ treatment. In the remaining participants, ingestion of BT vs. commercial grade CoQ significantly increased maximum plasma CoQ10 concentration (+126%, p = 0.04) and tended to increase CoQ10 area under the curve from 0 to 24 h (+160%, p = 0.07). One week of treatment with each formulation increased plasma CoQ10 but did not alter plasma glutathione or GPx activity. The enhanced bioavailability of the BT product might be due to its predominantly reduced, hydrophilic membrane-complex form.

Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects.

BACKGROUND: Many drugs are cosubstrates of cytochrome P450 (CYP) 3A and MDR1; furthermore, their disposition is markedly affected by pretreatment with inducing agents, including St John's wort. Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor. However, the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown. METHODS: The effects of 12 days' pretreatment with St John's wort on the disposition of selected in vivo probe drugs were determined in 21 young healthy subjects. Midazolam after oral and intravenous administration was used to assess CYP3A activity in both the intestinal epithelium and the liver, whereas the disposition of fexofenadine after an oral dose was assumed to be a measure of MDR1 function, and the oral plasma concentration-time profile of cyclosporine (INN, ciclosporin) was considered to reflect both CYP3A and MDR1 activities. RESULTS: St John's wort markedly affected the plasma concentration-time profiles of all of the drugs, with associated increases in their clearance. With midazolam, the enhancement was considerably less after intravenous administration (approximately 1.5-fold) than after oral administration (approximately 2.7-fold), and estimated intestinal and hepatic extraction ratios were higher by approximately 1.2- to 1.4-fold. By contrast, the oral clearances of fexofenadine and cyclosporine were equally increased by approximately 1.6-fold and 1.9-fold, respectively; these changes were both statistically less than for midazolam's oral clearance and greater than its estimated intestinal extraction. CONCLUSIONS: Although the disposition of all 3 drugs was altered by St John's wort, the extent of induction measured by oral clearance was different with CYP3A activity (midazolam), apparently increasing more than MDR1 function (fexofenadine), whereas with cyclosporine the change in oral clearance appeared to be more closely associated with the increase in MDR1 rather than CYP3A, despite the fact that both proteins are importantly involved in its disposition. These discordances indicate that, although a common molecular mechanism may be involved, the quantitative aspects of induction are complex and depend on the particular drug and the relative contributions of CYP3A and MDR1 in its disposition.

Evaluation of peppermint oil and ascorbyl palmitate as inhibitors of cytochrome P4503A4 activity in vitro and in vivo.

OBJECTIVES: Our study was designed to determine the effect of peppermint oil and ascorbyl palmitate on cytochrome P4503A4 (CYP3A4) activity in vitro and oral bioavailability of felodipine in humans. METHODS: Reversible and mechanism-based inhibitions of nifedipine oxidation were studied in human liver microsomes. The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined in 12 healthy volunteers after administration of felodipine, 10-mg extended-release tablet, with grapefruit juice (300 mL), peppermint oil (600 mg), ascorbyl palmitate (500 mg), or water in a randomized 4-way crossover study. RESULTS: Peppermint oil (inhibition constant [K(i)] = 35.9 +/- 3.3 microg/mL, mean +/- SEM) and 2 constituents, menthol (K(i) = 87.0 +/- 7.0 micromol/L), and menthyl acetate (K(i) = 124.0 +/- 7.0 micromol/L), produced reversible inhibition of nifedipine oxidation. Ascorbyl palmitate was more potent (K(i) = 12.3 +/- 0.5 micromol/L). None of these substances were mechanism-based inhibitors. Grapefruit juice and peppermint oil increased the area under the curve (AUC) values of felodipine to 173% (range, 94%-280%; P <.01) and 140% (range, 77%-262%; P <.05), respectively, of those with water. They augmented the peak plasma concentration (C(max)) of felodipine and the AUC and C(max) of dehydrofelodipine but did not alter the half-life (t(1/2)) of either substance. Grapefruit juice decreased the dehydrofelodipine/felodipine AUC ratio, but peppermint oil did not. Ascorbyl palmitate did not change the pharmacokinetics of felodipine or dehydrofelodipine compared with water. CONCLUSIONS: Peppermint oil, menthol, menthyl acetate, and ascorbyl palmitate were moderately potent reversible inhibitors of in vitro CYP3A4 activity. Grapefruit juice increased the oral bioavailability of felodipine by inhibition of CYP3A4-mediated presystemic drug metabolism. Peppermint oil may also have acted by this mechanism. However, this requires further investigation. Ascorbyl palmitate did not inhibit CYP3A4 activity in vivo.

A basic conceptual and practical overview of interactions with highly prescribed drugs.

Drug interactions are frequently the result of altered activity of the mechanism(s) responsible for drug elimination. These include drug metabolism mediated by a select group of cytochrome P450 enzymes (CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2) and drug transporters (P-glycoprotein). Adverse drug interactions can result from induction (loss of therapeutic benefit) or inhibition (increased toxicity from excessive effect) of drug elimination. CYPs and P-glycoprotein are discussed individually with regards to their characteristics, frequently prescribed drug substrates, inducers and inhibitors, and important adverse drug events. The potential for important drug interactions can be predicted based on the properties of the causative agent (oral bioavailability, mechanism of elimination, seriousness of adverse event) and the interacting agent. Consequently, drug interactions can be prevented by avoiding concomitant administration of interacting substances or possibly implementing alternative therapeutic strategies. Furthermore, susceptibility to adverse events depends not only on the interacting substances, but also on the patient and the method of drug administration. Commonly prescribed drugs that are unlikely to cause a drug interaction involving CYPs or P-glycoprotein are also discussed.