Vitamin D in Melanoma: Potential Role of Cytochrome P450 Enzymes.

Vitamin D is a promising anticancer agent for the prevention and treatment of several cancers, including melanoma. Low 25-hydroxyvitamin D levels, a routinely used marker for vitamin D, have been suggested as one of the factors in the development and progression of melanoma. The parent vitamin D needs activation by cytochrome P450 (CYP) enzymes to exert its actions via the vitamin D receptor (VDR). This review discusses the role of vitamin D in melanoma and how CYP-mediated metabolism can potentially affect the actions of vitamin D. Through interacting with the retinoid X receptor, VDR signaling leads to anti-inflammatory, antioxidative, and anticancer actions. Calcitriol, the dihydroxylated form of vitamin D3, is the most active and potent ligand of VDR. CYP27A1, CYP27B1, and CYP2R1 are involved in the activation of vitamin D, whereas CYP24A1 and CYP3A4 are responsible for the degradation of the active vitamin D. CYP24A1, the primary catabolic enzyme of calcitriol, is overexpressed in melanoma tissues and cells. Several drug classes and natural health products can modulate vitamin D-related CYP enzymes and eventually cause lower levels of vitamin D and its active metabolites in tissues. Although the role of vitamin D in the development of melanoma is yet to be fully elucidated, it has been proposed that melanoma prevention may be significantly aided by increased vitamin D signaling. Furthermore, selective targeting of the catabolic enzymes responsible for vitamin D degradation could be a plausible strategy in melanoma therapy. Vitamin D signaling can be improved by utilizing dietary supplements or by modulating CYP metabolism. A positive association exists between the intake of vitamin D supplements and improved prognosis for melanoma patients. Further investigation is required to determine the function of vitamin D supplementation and specific enzyme targeting in the prevention of melanoma.

Inappropriate Use of Proton Pump Inhibitor Among Elderly Patients in British Columbia: What are the Long-term Adverse Events?

BACKGROUND: Proton pump inhibitors (PPIs) are one of the most used classes of drugs. For most indications, PPIs are only recommended up to 8 weeks duration. However, PPI use continues to expand. Regular and prolonged use of PPIs should be avoided because of the risk of adverse events. OBJECTIVES: The main objective of this study was to (1) investigate the extent of PPI usage in people aged 65 or older in the province of British Columbia (BC), Canada, (2) provide an overview of the harms associated with the long-term use of PPIs. METHODS: We examined utilization trends of the PPIs in BC since the year 2009 using PharmaNet, BC's medication dispensing database where the information is accessible to community pharmacists. We performed a comprehensive literature search for relevant reviews reporting harms associated with long-term use of PPIs. A search was conducted from January 2014 to June 2022. RESULTS: Between 2000 and 2018 BC's population grew by 20%, but the use of PPIs escalated to 257%. Of these older British Columbians, 62% had a cumulative exposure exceeding 2 years and 42% exceeded 5 years. This is alarming because the recommended treatment duration is 4-12 weeks for common indications including reflux esophagitis, and duodenal and gastric ulcers. Only 13.5% were dispensed PPIs for 90 days or less. Patients on long-term PPI therapy should be reassessed. Adverse events of PPI use are common among older adults. We identified over 217 systematic reviews published during the last 8 years of specific harms associated with long-term daily usage of PPIs. These harms include increased risks of death, cardiovascular disease, acute renal injury, chronic kidney disease, dementia, fractures, hypomagnesemia, iron deficiency, vitamin B12 deficiency, enteric infection (including C. difficile), pneumonia, and neoplasia (gastric cancer, carcinoids, and colon cancer), and drug interactions. CONCLUSION: This study revealed a high prevalence of PPI use among elderly populations in BC, Canada. The overutilization of PPIs is often a result of failure to re-evaluate the need for continuation of therapy. Published studies identified signals of serious harm from long-term PPI exposure. Healthcare providers with patients can reverse the relentless expansion of long-term PPI exposure by discussing the expected benefits and potential harms.

Pharmacokinetics and pharmacodynamics of Rh2 and aPPD ginsenosides in prostate cancer: a drug interaction perspective.

Ginsenoside Rh2 and its aglycon (aPPD) are one of the major metabolites from Panax ginseng. Preclinical studies suggest that Rh2 and aPPD have antitumor effects in prostate cancer (PCa). Our aims in this review are (1) to describe the pharmacokinetic (PK) properties of Rh2 and aPPD ginsenosides; 2) to provide an overview of the preclinical findings on the use of Rh2 and aPPD in the treatment of PCa; and (3) to highlight the mechanisms of its PK and pharmacodynamic (PD) drug interactions. Increasing evidence points to the potential efficacy of Rh2 or aPPD for PCa treatment. Based on the laboratory studies, Rh2 or aPPD combinations revealed an additive or synergistic interaction or enhanced sensitivity of anticancer drugs toward PCa. This review reveals that enhanced anticancer activities were demonstrated in preclinical studies through interactions of Rh2 and/or aPPD with the proteins related to PK (e.g., cytochrome P450 enzymes, transporters) or PD of the other anticancer drugs or PCa signaling pathways. In conclusion, combining Rh2 or aPPD with anti-prostate cancer drugs leads to PK or PD interactions which could facilitate either therapeutically beneficial or toxic effects.

Cannabinoids for symptom management in children with cancer: A systematic review and meta-analysis.

BACKGROUND: Despite the widespread use of medical cannabis, little is known regarding the safety, efficacy, and dosing of cannabis products in children with cancer. The objective of this study was to systematically appraise the existing published literature for the use of cannabis products in children with cancer. METHODS: This systematic review, registered with the International Prospective Register of Systematic Reviews (CRD42020187433), searched four databases: MEDLINE, Embase, PsycINFO, and the Cochrane Library. Abstracts and full texts were screened in duplicate. Data on types of cannabis products, doses, formulations, frequencies, routes of administration, indications, and clinical and demographic details as well as reported efficacy outcomes were extracted. Data on cannabinoid-related adverse events were also summarized. RESULTS: Out of 34,611 identified citations, 19 unique studies with a total of 1927 participants with cancer were included: eight retrospective chart reviews, seven randomized controlled trials, two open-label studies, and two case reports. The included studies reported the use of various cannabis products for the management of symptoms. Cannabinoids were commonly used for the management of chemotherapy-induced nausea and vomiting (11 of 19 [58%]). In controlled studies, somnolence, dizziness, dry mouth, and withdrawal due to adverse events were more commonly associated with the use of cannabinoids. Across all included studies, no serious cannabis-related adverse events were reported. CONCLUSIONS: Although there is evidence to support the use of cannabis for symptom management, in children with cancer, there is a lack of rigorous evidence to inform the dosing, safety, and efficacy of cannabinoids. Because of the increasing interest in using cannabis, there is an urgent need for more research on medical cannabis in children with cancer.

Pharmacological Significance of Heme Oxygenase 1 in Prostate Cancer.

Heme oxygenase 1 (HO-1) is a detoxifying antioxidant microsomal enzyme that regulates inflammation, apoptosis, cell proliferation, and angiogenesis in prostate cancer (PCa). This makes HO-1 a promising target for therapeutic prevention and treatment due to its anti-inflammatory properties and ability to control redox homeostasis. Clinical evidence highlights the possible correlation between HO-1 expression and PCa growth, aggressiveness, metastasized tumors, resistance to therapy, and poor clinical outcomes. Interestingly, studies have reported anticancer benefits mediated by both HO-1 induction and inhibition in PCa models. Contrasting evidence exists on the role of HO-1 in PCa progression and possible treatment targets. Herein, we provide an overview of available evidence on the clinical significance of HO-1 signaling in PCa. It appears that the beneficial effects of HO-1 induction or inhibition are dependent on whether it is a normal versus malignant cell as well as the intensity (major vs. minor) of the increase in HO-1 enzymatic activity. The current literature evidence indicates that HO-1 has dual effects in PCa. The amount of cellular iron and reactive oxygen species (ROS) can determine the role of HO-1 in PCa. A major increase in ROS enforces HO-1 to a protective role. HO-1 overexpression may provide cryoprotection to normal cells against oxidative stress via suppressing the expression of proinflammatory genes, and thus offer therapeutic prevention. In contrast, a moderate increase in ROS can lead to the perpetrator role of HO-1, which is associated with PCa progression and metastasis. HO-1 inhibition by xenobiotics in DNA-damaged cells tilts the balance to promote apoptosis and inhibit PCa proliferation and metastasis. Overall, the totality of the evidence revealed that HO-1 may play a dual role in the therapeutic prevention and treatment of PCa.

Effect of Dexamethasone on Abiraterone Pharmacokinetics in Mice: Determined by LC/MS Analysis.

Background: Abiraterone acetate is a cytochrome P450 17A1 (CYP17A1) inhibitor that is indicated for use in both castration-resistant and castration-sensitive prostate cancer patients. To manage the mineralocorticoid effects of CYP17A1 inhibition, a glucocorticoid such as dexamethasone is co-administered with abiraterone. The goal of the present study was to understand the effect of dexamethasone on the disposition of abiraterone. Methods: Adult male CD-1 mice were treated with either dexamethasone (80 mg/kg/day) or vehicle for three consecutive days, followed by the administration of a single dose of abiraterone acetate (180 mg/kg) as an oral gavage. Blood samples were collected by tail bleeding at timepoints between 0 to 24 h. Subsequently, abiraterone was extracted from the mouse serum using a neutral pH condition and serum abiraterone levels were determined using a liquid chromatography-mass spectrometry assay. Results: Our results demonstrated that dexamethasone lowered the maximum plasma concentration and area under the curve parameters by approximately five- and ten-fold, respectively. Similar effects were also observed on the plasma half-life and oral clearance parameters. This is the first report of dexamethasone effect on abiraterone disposition in vivo. Conclusions: We conclude that dexamethasone has the potential to reduce the plasma abiraterone level and thus compromise its CYP17A1 inhibitory ability in the procancerous androgen biosynthesis pathway. Thus, use of a higher abiraterone dose may be warranted when used alongside dexamethasone.

Association between Vitamin D Status and Risk of Developing Severe COVID-19 Infection: A Meta-Analysis of Observational Studies.

OBJECTIVE: The relationship between 25-hydroxyvitamin D3 (25(OH)D), the surrogate marker for vitamin D3, serum concentration and COVID-19 has come to the forefront as a potential pathway to improve COVID-19 outcomes. The current evidence remains unclear on the impact of vitamin D status on the severity and outcomes of COVID-19 infection. To explore possible association between low 25(OH)D levels and risk of developing severe COVID-19 (i.e. need for invasive mechanical ventilation, the length of hospital stay, total deaths). We also aimed to understand the relationship between vitamin D insufficiency and elevated inflammatory and cardiac biomarkers. METHODS: We conducted a comprehensive electronic literature search for any original research study published up to March 30, 2021. For the purpose of this review, low vitamin D status was defined as a range of serum total 25(OH)D levels of <10 to <30 ng/ml. Two independent investigators assessed study eligibility, synthesized evidence, analyzed, critically examined, and interpreted herein. RESULTS: Twenty-four observational studies containing 3637 participants were included in the meta-analysis. The mean age of the patients was 61.1 years old; 56% were male. Low vitamin D status was statistically associated with higher risk of death (RR, 1.60 (95% CI, 1.10-2.32), higher risk of developing severe COVID-19 pneumonia (RR: 1.50; 95% CI, 1.10-2.05). COVID-19 patients with low vitamin D levels had a greater prevalence of hypertension and cardiovascular diseases, abnormally high serum troponin and peak D-dimer levels, as well as elevated interleukin-6 and C-reactive protein than those with serum 25(OH)D levels ≥30 ng/ml. CONCLUSIONS: In this meta-analysis, we found a potential increased risk of developing severe COVID-19 infection among patients with low vitamin D levels. There are plausible biological mechanisms supporting the role of vitamin D in COVID-19 severity. Randomized controlled trials are needed to test for potential beneficial effects of vitamin D in COVID-19 outcomes.

Anti-Tumor Effects of Ginsenoside 20(S)-Protopanaxadiol and 1,25-Dihydroxyvitamin D3 Combination in Castration Resistant Prostate Cancer.

In spite of possessing desirable anticancer properties, currently, limited clinical success has been achieved with 20(S)-protopanaxadiol (aPPD) and 1,25-dihydroxyvitamin D3 (calcitriol). This study is designed to evaluate if the combination of aPPD with calcitriol can inhibit human prostate cancer xenograft growth by using nuclear receptor signaling. Athymic male nude mice were utilized to establish an androgen-independent human prostate cancer C4-2 cell castration-resistant prostate cancer (CRPC) xenograft model. Mice were treated orally for six weeks with 70 mg/kg aPPD administered once daily or three times per week with 4 µg/kg calcitriol or in combination or only with vehicle control. Contrary to our expectations, calcitriol treatment alone increased C4-2 tumor growth. However, the addition of calcitriol substantially increased aPPD-mediated tumor growth suppression (76% vs. 53%, combination vs. aPPD alone). The combination treatment significantly increased levels of cleaved caspase-3 apoptotic marker compared to vehicle-treated or aPPD-treated C4-2 tumors. The mechanistic elucidations indicate that tumor inhibition by the aPPD and calcitriol combination was accompanied by elevated vitamin D receptor (VDR) protein expression. In silico data suggest that aPPD weakly binds to the native LBD pocket of VDR. Interestingly, the combination of aPPD and calcitriol activated VDR at a significantly higher level than calcitriol alone and this indicates that aPPD may be an allosteric activator of VDR. Overall, aPPD and calcitriol combination significantly inhibited tumor growth in vivo with no acute or chronic toxic effects in the C4-2 xenograft CRPC nude mice. The involvement of VDR and downstream apoptotic pathways are potential mechanistic routes of antitumor effects of this combination.

1α,25-Dihydroxyvitamin D3 synergistically enhances anticancer effects of ginsenoside Rh2 in human prostate cancer cells.

1α,25-dihydroxyvitamin D3 (1,25(OH)2D3, commonly known as calcitriol), the most active metabolite of vitamin D3, and ginsenoside Rh2 can regulate cellular differentiation and proliferation proteins. The purpose of the present study was to assess the effect of 1,25(OH)2D3 on the anticancer activities of Rh2 in human prostate cancer cells such as androgen-dependent LNCaP and androgen-independent C4-2 in vitro. The effects of treatment with 1,25(OH)2D3 or Rh2, either alone or in combination, on prostate cancer cells were evaluated through tetrazolium-based cell viability assay, BrdU cell proliferation rate estimation assay, and Western blot protein expression analyses of nuclear receptors (androgen receptor and vitamin D receptors) and apoptotic proteins (Bcl-2, Bax, and Caspase 3). The Combination Indices (CI) and Dose Reduction Indices (DRI) of 1,25(OH)2D3 and Rh2 were calculated to determine synergistic anticancer activity using Calcusyn software (Biosoft, Cambridge, UK). The cell viability assay data indicate that Rh2 treatment alone inhibited cell viability in a concentration-dependent manner and the addition of 10 nM 1,25(OH)2D3 to Rh2 significantly enhanced its ability to reduce cell viability up to 80 % in both the cell lines. Similarly, addition of 10 nM 1,25(OH)2D3 to Rh2 significantly lowered its IC50 values for cell proliferation from the range of 32-65 µM to 14-8 µM in LNCaP and C4-2 cells. In addition, protein expression analyses indicated that the combined treatment with Rh2 and 1,25(OH)2D3 led to greater downregulation of androgen receptor expression compared to single agent exposure. Similarly, the presence of 1,25(OH)2D3 synergistically increased the pro-apoptotic actions of Rh2 in both the cell lines. Overall, 1,25(OH)2D3 augments the Rh2-mediated anticancer effects through stimulating apoptosis and reduced cell proliferation which suggests that synergism of this combination may lead to potential lower need of the active vitamin D3 and limited toxicity from it.

Pharmacokinetic interaction of calcitriol with 20(S)-protopanaxadiol in mice: Determined by LC/MS analysis.

The physiological and anti-cancer functions of vitamin D3 are accomplished primarily via 1α,25-dihydroxyvitamin D3 (calcitriol), whereas 20(S)-protopanaxadiol (aPPD) is a ginsenoside, which is isolated from Panax ginseng, with potential anti-cancer benefits. In the present study, we report a pharmacokinetic (PK) herb-nutrient interaction between calcitriol and aPPD in mice. A liquid chromatography mass spectrometry (LC/MS) method was developed using 4-phenyl-1,2,4-triazoline-3,5-dione derivatizing agent and we subsequently used the method to quantitate calcitriol in mouse serum. The limit of quantitation was 0.01 ng/ml which is approximately 100 fold lower than the previously reported assay from our laboratory. Calcitriol PK parameters were determined in non-tumor-bearing or C4-2 human prostate tumor-bearing nude mice following oral co-administration of calcitriol either alone or in combination with aPPD. Mice were pretreated with oral aPPD (70 mg/kg) or vehicle control twice daily for seven consecutive days, followed by a single oral dose of 4 µg/kg calcitriol alone or in combination with aPPD. Our PK results demonstrated that co-administration of calcitriol with aPPD (following pre-treatment with vehicle for seven days) resulted in a 35% increase in the area under the curve (AUC0-24 h) and a 41% increase in the maximum serum concentration (Cmax) compared to the calcitriol only group. aPPD therefore significantly increased calcitriol serum exposure. We also saw a reduction in the time required to reach Cmax. In contrast, calcitriol PK in mice co-administered with calcitriol and aPPD as well as those pretreated seven consecutive days with aPPD was no different than that determined for the mice that received vehicle for seven days as pre-treatment. Co-administration of calcitriol with aPPD therefore could increase health benefits of vitamin D3, however any increased risk of hypercalcemia, resulting from this combination approach, requires further investigation. Lastly, we surmise that a cytochrome P450 inhibition-based mechanism may contribute to the observed PK interaction.

20(S)-protopanaxadiol regio-selectively targets androgen receptor: anticancer effects in castration-resistant prostate tumors.

We have explored the effects of 20(S)-protopanaxadiol (aPPD), a naturally derived ginsenoside, against androgen receptor (AR) positive castration resistant prostate cancer (CRPC) xenograft tumors and have examined its interactions with AR. In silico docking studies for aPPD binding to AR, alongside transactivation bioassays and in vivo efficacy studies were carried out in the castration-resistant C4-2 xenograft model. Immunohistochemical (IHC) and Western blot analyses followed by evaluation of AR, apoptotic, cell cycle and proliferative markers in excised tumors was performed. The growth of established CRPC tumors was inhibited by 53% with aPPD and a corresponding decrease in serum PSA was seen compared to controls. The IHC data revealed that Ki-67 was significantly lower for aPPD treated tumors and was associated with elevated p21 and cleaved caspase-3 expression, compared to vehicle treatment. Furthermore, aPPD decreased AR protein expression in xenograft tumors, while significantly upregulating p27 and Bax protein levels. In vitro data supporting this suggests that aPPD binds to and significantly inhibits the N-terminal or the DNA binding domains of AR. The AR androgen binding site docking score for androgen (dihydrotestosterone) was -11.1, while that of aPPD was -7.1. The novel findings described herein indicate aPPD potently inhibits PCa in vivo partly via inhibition of a site on the AR N-terminal domain. This manifested as cell cycle arrest and concurrent induction of apoptosis via an increase in Bax, cleaved-caspase-3, p27 and p21 expression.

Calcitriol in Combination Therapy for Prostate Cancer: Pharmacokinetic and Pharmacodynamic Interactions.

Epidemiological studies indicate that vitamin D insufficiency could have an etiological role in prostate cancer. In addition, calcitriol, used in combination with currently available drugs, has the potential to potentiate their anticancer effects or act synergistically by inhibiting distinct mechanisms involved in prostate cancer growth. Clinical data have not yet provided sufficient evidence to demonstrate benefit of vitamin D due to the limited and underpowered studies that have been published to date. Here, we review the preclinical and clinical studies that describe the activity of calcitriol, applied either alone or in combination and assessed the mechanistic basis of pharmacodynamic and pharmacokinetic interactions with calcitriol. Important considerations for calcitriol use in combination therapy with respect to safety and clinical outcomes have been discussed. Many of these combinations have therapeutic potential for the treatment of several cancer types and it is anticipated that future clinical research will put emphasis on well­designed clinical trials to establish efficacy.

Calcitriol and 20(S)-protopanaxadiol synergistically inhibit growth and induce apoptosis in human prostate cancer cells.

The potential cancer preventive roles of calcitriol, the dihydroxylated metabolite of Vitamin D3, as well as 20(S)-protopanaxadiol (aPPD), the aglycone of the protopanaxadiol family of ginsenosides, have gained much attention in recent years for the prevention/treatment of prostate cancer (PCa). In the present study, we evaluated the anticancer and chemosensitization effects of calcitriol at clinically relevant concentrations and aPPD, either alone or in combination, in two well-characterized human PCa cell lines: androgen-sensitive non-metastatic LNCaP cells and androgen-independent metastatic C4-2 cells. The effects of the treatments on PCa cell viability and proliferation rates were evaluated by MTS and Brdu assays, respectively. Combination Indices (CI) and Dose Reduction Indices (DRI) were estimated to assess synergistic anticancer activity using Calcusyn software (Biosoft, Cambridge, UK). Then, we determined the potential Pharmacodynamic interaction mechanisms as follows: The protein expression levels of the genes those are known to control cell cycle (cyclin D1 and cdk2); apoptosis (Bcl-2, Bax, and Capspases 3), androgen receptor and Vitamin D receptors were examined upon combinational treatment. The cell viability assay data show that addition of 10nM calcitriol to aPPD significantly lowered its IC50 values from the range of 41-53µM to 13-23µM, in LNCaP and C4-2 prostate cancer cells. The cell proliferation rate was significantly lower for combination treatments compared to the cells treated with aPPD alone. Similarly, Western blot results indicate that aPPD significantly upregulated Vitamin D receptor (VDR) expression, while calcitriol further enhanced the ability of aPPD to induce pro-apoptotic BAX, increased cleaved caspase-3 and downregulate cdk2 protein levels. Thus, the pharmacodynamic interaction between aPPD and calcitriol in impacting growth inhibition and apoptosis appears to be synergistic in nature. In conclusion, calcitriol sensitizes PCa cells to aPPD-mediated anticancer effects by enhancing its ability to induce apoptosis and reduce cell proliferation, and this synergism may limit calcitriol toxicity by facilitating the use of lower calcitriol doses. The associated increase in VDR expression and calcitriol half-life may be mechanistically associated with this sensitization effect.

Effect of rat serum lipoproteins on mRNA levels and amiodarone metabolism by cultured primary rat hepatocytes.

Hyperlipidemia can significantly increase amiodarone (AM) in vivo liver uptake and decrease its velocity of microsomal metabolism. Here, hepatocytes isolated from normolipidemic (NL) and hyperlipidemic rats were incubated with AM in the presence or absence of diluted NL or hyperlipidemic serum. The serum was added either as preincubation before drug, or concurrently with drug; incubations without rat serum were used as controls. The hepatocyte levels of mRNA for several proteins and enzymes were also measured. Disappearance of AM was seen up to 72 h. There was little difference between hepatocytes from NL or hyperlipidemic animals in intrinsic clearance (CL(int) ) of AM. The effect of hyperlipidemic rat serum, either before or with AM, was profound, causing a significant reduction in the CL(int) . Reductions were seen in mRNA for cytochrome P450 1A1, 3A2, and 2D1, some transporters, and low-density lipoprotein receptors after exposure of hepatocytes to lipoprotein-rich sera. In conclusion, exposure of isolated hepatocytes to hyperlipidemic serum caused decreases in AM CL(int) and lower mRNA levels for some proteins involved in the uptake and metabolism of AM. When coincubated with serum, an additional effect of increased binding to lipoproteins seemed to further contribute to a reduced CL of AM.

The effects of gastric bypass surgery on drug absorption and pharmacokinetics.

INTRODUCTION: Being overweight is widespread in most societies and represents a major health threat. Gastric bypass surgery offers a highly effective mode of treatment for the morbidly obese patients. The procedures cause an alteration in normal gastrointestinal anatomy and physiology, with consequences not only on nutrient absorption, but also possibly on orally administered drugs. Bypass of the acidic environment of the stomach, partial impairment of bile salts-drug interactions and reduced absorptive surface, all create the potential for reduced absorption of drugs. AREAS COVERED: This article provides an overview of the effects of obesity and the most prevalent type of gastric bypass (Roux-en-Y) on pharmacokinetics. Articles for review were searched using Pubmed. EXPERT OPINION: The absorption of those drugs with known bioavailability issues generally seem to be most affected by bypass surgery. It is important to consider the effect of obesity on pharmacokinetics independent of the bypass procedure, because it leads to a dramatic drop in body mass over a relatively short period of time. This may be associated with reversals in the influence of obesity on drug disposition to characteristics more in line with leaner patients. Drugs will differ in their pharmacokinetic response to surgery, limiting any general conclusions regarding the impact of the surgery on drug disposition.

Effect of gastric bypass surgery on azithromycin oral bioavailability.

OBJECTIVES: Azithromycin is used widely for community-acquired infections. The timely administration of azithromycin in adequate doses minimizes treatment failure. Gastric bypass, a procedure that circumvents the upper gut, may compromise azithromycin plasma levels. We hypothesized that azithromycin concentrations would be reduced following gastric bypass. METHODS: A single-dose pharmacokinetic study in 14 female post-gastric bypass patients and 14 sex- and body mass index (BMI)-matched controls (mean age 44 years and BMI 36.4 kg/m(2)) was performed. Subjects were administered two 250 mg azithromycin tablets at time 0 and plasma azithromycin levels were sampled at 0.5, 1, 1.5, 2, 3, 5, 7 and 24 h. The AUC of the plasma azithromycin concentrations from time 0 to 24 h (AUC(0-24)) was the primary outcome. RESULTS: Azithromycin concentrations were lower in gastric bypass patients compared with controls throughout the entire duration of sampling. Compared with controls, the AUC(0-24) was reduced in gastric bypass subjects by 32% [1.41 (SD 0.51) versus 2.07 (0.75) mg ·â€Šh/L; P = 0.008], and dose-normalized AUC(0-24) was reduced by 33% [0.27 (0.12) versus 0.40 (0.13) kg ·â€Šh/L; P = 0.009]. Peak azithromycin concentrations were 0.260 (0.115) in bypass subjects versus 0.363 (0.200) mg/L in controls (P = 0.08), and were reached at 2.14 (0.99) h in gastric bypass subjects and 2.36 (1.17) h in controls (P = 0.75). CONCLUSIONS: Azithromycin AUC was reduced by one-third in gastric bypass subjects compared with controls. The potential for early treatment failure exists, and dose modification and/or closer clinical monitoring of gastric bypass patients receiving azithromycin should be considered.