Thriving or surviving? A critical examination of funding models for fellowship council fellowships.

BACKGROUND: Since 1997, the Fellowship Council (FC) has evolved into a robust organization responsible for the advanced training of nearly half of the US residency graduates entering general surgery practice. While FC fellowships are competitive (55% match rate) and offer outstanding educational experiences, funding is arguably vulnerable. This study aimed to investigate the current funding models of FC fellowships. METHODS: Under an IRB-approved protocol, an electronic survey was administered to 167 FC programs with subsequent phone interviews to collect data on total cost and funding sources. De-identified data were also obtained via 2020-2021 Foundation for Surgical Fellowships (FSF) grant applications. Means and ranges are reported. RESULTS: Data were obtained from 59 programs (35% response rate) via the FC survey and 116 programs via FSF applications; the average cost to train one fellow per year was $107,957 and $110,816, respectively. Most programs utilized departmental and grants funds. Additionally, 36% (FC data) to 39% (FSF data) of programs indicated billing for their fellow, generating on average $74,824 ($15,000-200,000) and $33,281 ($11,500-66,259), respectively. FC data documented that 14% of programs generated net positive revenue, whereas FSF data documented that all programs were budget-neutral. CONCLUSION: Both data sets yielded similar overall results, supporting the accuracy of our findings. Expenses varied widely, which may, in part, be due to regional cost differences. Most programs relied on multiple funding sources. A minority were able to generate a positive revenue stream. Although fewer than half of programs billed for their fellow, this source accounted for substantial revenue. Institutional support and external grant funding have continued to be important sources for the majority of programs as well. Given the value of these fellowships and inherent vulnerabilities associated with graduate medical education funding, alternative grant funding models and standardization of annual financial reporting are encouraged.

Multidisciplinary Simulation Activity Effectively Prepares Residents for Participation in Patient Safety Activities.

PURPOSE: In 2017, The Accreditation Council for Graduate Medical Education (ACGME) issued Common Program Requirements that stipulated residents must participate in real or simulated interprofessional patient safety activities, such as root cause analyses (RCA). The requirements also stated that residents should have the opportunity to participate in the disclosure of patient safety events. Our institution supports a large graduate medical education (GME) cohort with approximately 1400 GME learners in more than 100 ACGME programs. Knowing that our university hospital system conducts approximately 15 RCA's per year, our GME leadership charged the Dean of Simulation with developing a pilot simulation activity that would satisfy these educational needs. METHODS: Four departments (Anesthesia, Emergency Medicine, OB/GYN, and Surgery) assigned a total of 39 learners to participate in the pilot simulation. Learners were divided into groups of 5 to 8 participants representing at least 3 departments. Before the simulation, learners were asked to complete a preactivity questionnaire rating their comfort with the learning objectives and a 10-question multiple choice quiz assessing knowledge of RCA principles. The simulation was 1-hour long and consisted of 2 parts. First, learners participated in a high-fidelity, mannequin-based resuscitation scenario that was scripted to include systems barriers to effective resuscitation. Second, our University Hospital's Vice President of Quality and Safety led participants in a simulated RCA analyzing the systems issues encountered. Finally, all learners completed a postactivity questionnaire and quiz. Preactivity and postactivity data were compared with repeated measures t-tests with p < 0.05 considered significant. RESULTS: Complete data were available for 38 learners. We observed significant improvements in quiz performance and learners' self-reported abilities to perform tasks related to patient safety and RCA. The simulation activity did not affect learners' anxiety regarding potential participation in an RCA. CONCLUSIONS: Our data indicate that a 1-hour, introductory-level simulation improved residents' confidence and knowledge related patient safety activities. This training format is efficient, effective, and consistent with the expectations of the new ACGME Common Program Requirement.

Incidental 99mTc MDP uptake in the intestines and intravenous CT contrast.

AIM: We evaluated the association between intestinal visualization on bone scintigraphy and IV CT contrast in patients with breast cancer. PATIENTS, METHODS: 452 patients with breast cancer underwent a 99mTc methylene diphosphonate (MDP) bone scan for surveillance of bone metastasis. Presence, site and intensity of intestinal uptake were visually assessed. For patients with intestinal visualization, medical records were reviewed to identify the alleged potential causes. When IV CT contrast was administrated on the same day as bone scan, the time between IV CT contrast injection, 99mTc MDP administration and bone scan was assessed. RESULTS: Intestinal 99mTc MDP uptake was observed in 44 of the 452 patients (9.7%). Bone scans showed no thyroid or gastric uptake that suggested free pertechnetate. There were no patients with documented causes of intestinal uptake except for one patient with vesicoenteric fistula. Of the 452 patients, 149 (33.0%) underwent IV contrast-enhanced CT on the same day as bone scan. Forty of the 44 patients (90.9%) with intestinal uptake on bone scan underwent IV contrast-enhanced CT on the same day, whereas 109 of 408 (26.7%) patients without intestinal uptake on bone scintigraphy underwent IV contrast-enhanced CT on the same day (p < 0.001). The patients who underwent IV contrast injection between Tc-99m MDP administration and acquisition of bone scans had significantly more frequent intestinal uptake than patients who underwent IV contrast injection either before 99mTc MDP administration or after bone scanning (42.4% vs. 1.8%, p < 0.001). CONCLUSIONS: IV CT contrast injection administered on the same day as bone scintigraphy is significantly associated with 99mTc MDP uptake in the intestines among patients with breast cancer.

The efficacy of steroids for edema and ecchymosis after rhinoplasty: a meta-analysis.

OBJECTIVES: Postoperative periorbital edema and ecchymosis following rhinoplasty can result in dissatisfaction for both the surgeon and the patient. The goal of this study was to perform a systematic review of the literature on the efficacy of steroids on edema and ecchymosis during rhinoplasty. DATA SOURCES: MEDLINE, SCOPUS, and Cochrane database. REVIEW METHODS: Two authors independently searched the databases from their inception of article collection to February 2014. Studies comparing perioperative steroid administration (steroid group) with no treatment (control group) where the outcomes of interest were edema and ecchymosis on postoperative days were included in the analysis. Overall, a total of nine trials met the inclusion criteria of this study, with a total sample size of 312 patients. RESULTS: The lower and upper eyelid edema during the 7 days postoperatively was statistically decreased in the steroid group versus control group. The lower and upper eyelid ecchymosis in the steroid group was significantly decreased in comparison to the control group for the first 4 days follow surgery. Regarding the outcome comparison between single-dose and multiple-dose administration of steroids, the multiple-dose administration decreased edema and ecchymosis significantly compared to single-dose administration after the fourth day. CONCLUSIONS: Perioperative administration of steroid during rhinoplasty could reduce the level of edema and eyelid ecchymosis. Multiple-dose administration of steroids has more advantages in terms of the outcomes of late postoperative edema and ecchymosis compared to a single-dose regimen.

The effects of shared situational awareness on functional and hospital outcomes of hospitalized older adults with heart failure.

BACKGROUND: Functional decline of hospitalized older adults is common and triggers health care expenditures. Physical therapy can retard the functional decline that occurs during hospitalization. This study aims to examine whether shared situational awareness (SSA) intervention may enhance the benefits of physical therapy for hospitalized older persons with a common diagnosis, heart failure. METHOD: An SSA intervention that involved daily multidisciplinary meetings was applied to the care of functionally declining older adults admitted to the medicine floor for heart failure. Covariates were matched between the intervention group (n=473) and control group (n=475). Both intervention and control groups received physical therapy for ≥0.5 hours per day. The following three outcomes were compared between groups: 1) disability, 2) transition to skilled nursing facility (SNF, post-acute care setting), and 3) 30-day readmission rate. RESULTS: Disability was lower in the intervention group (28%) than in the control group (37%) (relative risk [RR] =0.74; 95% confidence interval [CI], 0.35-0.97; P=0.026), and transition to SNF was lower in the intervention group (22%) than in the control group (30%) (RR =0.77; 95% CI, 0.39-0.98; P=0.032). The 30-day readmission rate did not significantly differ between the two groups. CONCLUSION: SSA intervention enhanced the benefits of physical therapy for functionally declining older adults. When applied to older adults with heart failure in the form of daily multidisciplinary meetings, SSA intervention improved functional outcomes and reduced transfer to SNFs after hospitalization.

Effects of morin on the pharmacokinetics of docetaxel in rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors.

Docetaxel is a P-glycoprotein (P-gp) substrate and metabolized via cytochrome P450 (CYP) 3A subfamily in rats. Morin is an inhibitor of both CYPs and P-gp. Hence, the effects of morin on the intravenous and oral pharmacokinetics of docetaxel were investigated using 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumor rats (DMBA rats) as an animal model of human breast cancer. Docetaxel was administered intravenously (4 mg/kg) and orally (20 mg/kg) without and with morin (15 mg/kg) in DMBA rats. After the intravenous administration of docetaxel in control and DMBA rats with and without morin, the values of non-renal clearance and area under the plasma concentration-time (AUC) for docetaxel were comparable. Morin did not increase AUC or the absolute oral bioavailability (F) for docetaxel after the oral administration of docetaxel in control and DMBA rats with and without morin. The inhibition of hepatic and intestinal metabolism of docetaxel by morin and/or DMBA and the effect of intestinal P-gp inhibition by morin on the pharmacokinetics of docetaxel did not seem to be considerable in DMBA-induced mammary tumor rats.

Roles of AKT1 and AKT2 in non-small cell lung cancer cell survival, growth, and migration.

Although AKT / protein kinase B is constitutively active in nonsmall cell lung cancer (NSCLC) cells and is an attractive target for enhancing the cytotoxicity of therapeutic agents, the distinct roles of the AKT isoforms in NSCLC are largely unknown. In the present study, we investigated the roles of AKT1 and AKT2 in NSCLC cells using RNAi. The siRNA targeting of AKT1 or AKT2 effectively decreased protein levels of AKT1 and AKT2, respectively, in A549 and H460 cells. Cisplatin treatment of these cells increased apoptotic cell death compared with control. The siRNA-induced knockdown of AKT1 in H460 cells significantly decreased basal MEK/ ERK1 / 2 activity, resulting in nuclear factor-κB activation, whereas knockdown of AKT2 resulted in anti-apoptotic Bcl-2 family protein MCL-1 (MCL-1) cleavage, the collapse of mitochondrial membrane potential, cytochrome c release, and activation of the caspase cascade. Consequently, both siRNA treatments enhanced the chemosensitivity of H460 cells to cisplatin. However, neither AKT1 nor AKT2 siRNA treatment had any effect of p27 expression, and although both treatments tended to induced G2 /M phase arrest, the effect was not statistically significant. Treatment with AKT1 siRNA markedly decreased colony formation growth and migration, but AKT2 siRNA had no significant effects on these parameters. These data suggest that AKT1 and AKT2 both contribute to cell survival, albeit via different mechanisms, and that the effects on cell growth and migration are predominantly regulated by AKT1. These findings may aid in refining targeted strategies for the inhibition of AKT isoforms towards the sensitization of NSCLC cells to therapeutic agents.

1,25-Dihydroxyvitamin D3 enhances NK susceptibility of human melanoma cells via Hsp60-mediated FAS expression.

The active metabolite of vitamin D(3), 1α,25(OH)(2)D(3) , displays anticancer effects by regulating cell cycle and apoptosis in many cancer cells. However, it has not been determined whether 1α,25(OH)(2)D(3) increases the susceptibility of cancer cells to NK cells. Here, we investigated the anticancer effect of 1α,25(OH)(2)D(3) in human melanoma cell lines by investigating enhancement of NK susceptibility and elucidating the mediator of NK cytotoxicity. 1α,25(OH)(2)D(3)-resistant melanoma cells (G-361 and SK-MEL-5) treated with 1α,25(OH)(2)D(3) showed higher susceptibility to NK cells with up-regulation of Fas expression. Furthermore, G-361 cells treated with 1α,25(OH)(2)D(3) showed significantly increased caspase activity. In addition to Fas up-regulation, expression of heat shock protein 60 (Hsp60) was elevated by 1α,25(OH)(2) D(3) . Increased expression of Hsp60 by 1α,25(OH)(2)D(3) was related to not only up-regulation of Fas expression but also to NK susceptibility of G-361 cells. Taken together, our data suggest that 1α,25(OH)(2)D(3) acts as an anticancer agent by increasing expression of Fas on the surface of melanoma cells through Hsp60 induction and strengthens caspase sensitivity to Fas-mediated apoptotic pathway by NK cells. 1α,25(OH)(2)D(3) treatment may therefore have a preventive role in melanoma occurrence or potentiate the anticancer effects of NK-cell immune therapy.

Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus.

OBJECTIVES: In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of metabolites, AUC(metabolite)/AUC(parent drug) ratios, or the time-averaged nonrenal and total body clearances (CL(NR) and CL, respectively) of parent drugs as reported in the literature have been compared. KEY FINDINGS: After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CL(int)) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster. SUMMARY: Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans.

Effects of tesmilifene, a substrate of CYP3A and an inhibitor of P-glycoprotein, on the pharmacokinetics of intravenous and oral docetaxel in rats.

OBJECTIVES: It has been reported that docetaxel is a P-glycoprotein substrate and is metabolized via the cytochrome P450 (CYP) 3A subfamily in rats. Tesmilifene is a substrate of the CYP3A subfamily and is an inhibitor of P-glycoprotein. Thus, the effects of various doses of tesmilifene on the pharmacokinetics of intravenous and orally administered docetaxel have been investigated in rats. METHODS: Docetaxel (20 mg/kg as base) was administered intravenously and orally without and with tesmilifene (5, 10, and 20 mg/kg) in rats. KEY FINDINGS: After intravenous administration of docetaxel with tesmilifene, the values of nonrenal clearance (CL(NR)) and area under the plasma concentration-time (AUC) for docetaxel were comparable with those without tesmilifene. Tesmilifene did not increase the values of AUC or of absolute oral bioavailability (F) for docetaxel after oral administration of docetaxel with tesmilifene. CONCLUSIONS: The inhibition for the metabolism of docetaxel via hepatic and intestinal CYP3A subfamily, and inhibition of P-glycoprotein-mediated efflux of docetaxel in the intestine by tesmilifene were almost negligible. The extremely low value of F for docetaxel was due to the incomplete absorption from the gastrointestinal tract and considerable first-pass metabolism of docetaxel in rats.

Dose-dependent pharmacokinetics of SP-8203 in rats.

The pharmacokinetics of SP-8203, a potential protective agent for the treatment of cerebral infarction, were evaluated after its intravenous (10, 20 and 30 mg/kg) and oral (10, 20, 30 and 100 mg/kg) administration in rats. After the intravenous administration of SP-8203, the AUCs of SP-8203 were dose-dependent; the dose-normalized AUCs were significantly greater with increasing doses. After the oral administration of SP-8203, plasma concentrations of SP-8203 were much lower than those after intravenous administration. This could be due to considerable hepatic and intestinal metabolism and the high percent of the dose recovered from the gastrointestinal tract (including its contents and feces) at 24 h as unchanged drug.

Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism.

OBJECTIVES: It has been reported that the non-renal clearance of furosemide was significantly faster in rats pretreated with phenobarbital but was not altered in rats pretreated with 3-methylcholanthrene. However, no studies on other cytochrome P450 (CYP) isozymes have yet been reported in rats. METHOD: Furosemide 20 mg/kg was administered intravenously to rats pretreated with various CYP inducers--3-methylcholanthrene, orphenadrine citrate and isoniazid, inducers of CYP1A1/2, 2B1/2 and 2E1, respectively, in rats--and inhibitors--SKF-525A (a non-specific inhibitor of CYP isozymes), sulfaphenazole, cimetidine, quinine hydrochloride and troleandomycin, inhibitors of CYP2C6, 2C11, 2D and 3A1/2, respectively, in rats. KEY FINDINGS: The non-renal clearance of furosemide was significantly faster (55.9% increase) in rats pretreated with isoniazid, but slower in those pretreated with cimetidine or troleandomycin (38.5% and 22.7% decreases, respectively), than controls. After incubation of furosemide with baculovirus-infected insect cells expressing CYP2C11, 2E1, 3A1 or 3A2, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2. CONCLUSIONS: These findings could help explain possible pharmacokinetic changes of furosemide in various rat disease models (where CYP2C11, 2E1, 3A1 and/or CYP3A2 are altered) and drug-drug interactions between furosemide and other drugs (mainly metabolized via CYP2C11, 2E1, 3A1 and/or 3A2).

Time-dependent effects of Klebsiella pneumoniae endotoxin on the telithromycin pharmacokinetics in rats; restoration of the parameters in 96-hour KPLPS rats to the control levels.

OBJECTIVES: It has been reported that telithromycin is primarily metabolized via hepatic CYP3A4 and 3A1/2 in humans and rats, respectively, and that the protein expression of hepatic CYP3A subfamily significantly decreased (59.1% decrease) in 24-h KPLPS rats (lipopolysaccharide derived from Klebsiella pneumoniae; the protein expression was measured 24h after KPLPS administration) compared with that in control rats, but restored to that in control rats in 96-h KPLPS rats. METHODS: The pharmacokinetic parameters of telithromycin were compared after intravenous and oral administration at a dose of 50mg/kg to control, 24-h KPLPS, and 96-h KPLPS rats. RESULTS: After both intravenous and oral administration of telithromycin to 24-h KPLPS rats, the AUC of telithromycin became significantly greater (68.2% and 88.7% increase for intravenous and oral administration, respectively) and this could have been due to the significantly slower CL(NR) (45.7% decrease). Because telithromycin is a low hepatic extraction ratio drug, the slower CL(NR) could have been due to the decreased protein expression of the hepatic CYP3A subfamily compared with that in control rats, and was supported by the significantly slower in vitro CL(int) in hepatic microsomes (13.1% decrease). However, in 96-h KPLPS rats, the pharmacokinetic parameters of telithromycin restored fully to those in control rats due to restoration of the protein expression of the hepatic CYP3A subfamily to that in control rats. The protein expression of the intestinal CYP3A subfamily was comparable among three groups of rats. CONCLUSIONS: These findings indicate the existence of the time-dependent effects of KPLPS on the pharmacokinetics of telithromycin in rats.

Telithromycin pharmacokinetics in rat model of diabetes mellitus induced by alloxan or streptozotocin.

PURPOSE: It has been reported that telithromycin is primarily metabolized via hepatic CYP3A1/2 in rats, the expression and/or mRNA level of hepatic CYP3A1/2 increase in rat model of diabetes mellitus induced by alloxan (DMIA) or streptozotocin (DMIS), and intestinal CYP3A1/2 enzyme activity decreases in rat model of DMIS. Thus, the pharmacokinetic changes of telithromycin in both models of diabetes mellitus compared with those in the control rats were evaluated. METHODS: Telithromycin was administered (50 mg/kg) intravenously or orally to both rat models of diabetes and their respective control rats. RESULTS: After intravenous administration of telithromycin to both models of diabetes, the non-renal clearance (CLNR) was significantly faster (32.3 and 53.1% increase for rat models of DMIA and DMIS, respectively) and the AUC was significantly smaller (25.0 and 33.8% decrease, respectively) than those in their respective controls. However, after oral administration of telithromycin, the AUC was comparable to that in their respective controls. CONCLUSIONS: The faster CLNR after intravenous administration was due to increased hepatic CYP3A1/2 in both models of diabetes. The comparable AUC after oral administration was mainly due to decreased intestinal CYP3A1/2 activity. Alloxan and streptozotocin appear to influence some pharmacokinetics of telithromycin in a different fashion.

Time-dependent effects of Klebsiella pneumoniae endotoxin (KPLPS) on the pharmacokinetics of theophylline in rats: return of the parameters in 96-hour KPLPS rats to the control levels.

It has been reported that theophylline is primarily metabolized via hepatic CYP1A1/2, 2B1/2, and 3A1/2, and 1,3-dimethyluric acid (1,3-DMU) is primarily formed via CYP1A1/2 in rats. Compared with control rats, the expression of CYP1A subfamily, 2B1/2, and 3A subfamily significantly decreased 24 h (24-h KPLPS rats) after intravenous administration of lipopolysaccharide derived from Klebsiella pneumoniae (KPLPS) to rats but returned to that in control rats after 96 h (96-h KPLPS rats). After intravenous or oral administration of theophylline to 24-h KPLPS rats, the values for the total area under the plasma concentration-time curve from time zero to time infinity of theophylline and 1,3-DMU became significantly greater (46.5 and 34.0% increase after intravenous and oral administration, respectively) and smaller (36.3 and 21.6% decrease, respectively), respectively. Because theophylline is a low hepatic extraction ratio drug in rats, the above results could have been due to significantly slower CL(int) for the disappearance of theophylline and for the formation of 1,3-DMU (37.1 and 60.6% decrease, respectively). However, in 96-h KPLPS rats, the pharmacokinetic parameters of theophylline and 1,3-DMU returned fully or partially to those in control rats. These findings indicate the existence of time-dependent effects of KPLPS on the pharmacokinetics of theophylline and 1,3-DMU in rats.

Effects of Escherichia coli lipopolysaccharide on telithromycin pharmacokinetics in rats: inhibition of metabolism via CYP3A.

It has been reported that telithromycin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP) 3A1/2 in rats and that the expression of hepatic and intestinal CYP3A decreases in rats pretreated with Escherichia coli lipopolysaccharide (ECLPS rats; an animal model of inflammation). Thus, it is possible that the area under the plasma concentration-time curve from 0 h to infinity (AUC 0-infinity) of intravenous and oral telithromycin is greater for ECLPS rats than for the controls. To assess this, the pharmacokinetic parameters of telithromycin were compared after intravenous and oral administration (50 mg/kg). After intravenous administration of telithromycin, the AUC 0-infinity was significantly greater (by 83.4%) in ECLPS rats due to a significantly lower nonrenal clearance (by 44.5%) than in the controls. This may have been due to a significantly decreased hepatic metabolism of telithromycin in ECLPS rats. After oral administration of telithromycin, the AUC 0-infinity in ECLPS rats was also significantly greater (by 140%) than in the controls and the increase was considerably greater than the 83.4% increase after intravenous administration. This could have been due to a decrease in intestinal metabolism in addition to a decreased hepatic metabolism of telithromycin in ECLPS rats.

Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU.

The types of hepatic cytochrome P450 (CYP) isozymes responsible for the metabolism of theophylline and for the formation of 1,3-dimethyluric acid (1,3-DMU) in rats in-vivo does not seem to have been studied at the dose ranges of dose-independent metabolic disposition of theophylline in rats (up to 10 mg kg(-1)). Therefore, theophylline (5 mg kg(-1)) was administered i.v. to male Sprague-Dawley rats pretreated with various inducers and inhibitors of CYP isozymes. In rats pretreated with 3-methylcholanthrene (3-MC), orphenadrine or dexamethasone (main inducers of CYP1A1/2, CYP2B1/2 and CYP3A1/2, respectively, in rats), the time-averaged non-renal clearance (CLNR) of theophylline was significantly faster than in their respective controls (1260, 42.7 and 69.0% increases, respectively). However, in rats pretreated with troleandomycin (a major inhibitor of CYP3A1/2 in rats), CLNR was significantly slower than in the controls (50.7% decrease). The 24 h urinary excretion of 1,3-DMU was increased significantly only in rats pretreated with 3-MC. The ratio of area under the curve for 1,3-DMU and theophylline (AUC1,3-DMU/AUCtheophylline) was increased significantly in rats pretreated with 3-MC (160% increase) and decreased significantly in rats pretreated with troleandomycin (50.1% decrease); however, the ratio was not increased in rats pretreated with dexamethasone. These data suggest that theophylline is primarily metabolized via CYP1A1/2, CYP2B1/2, and CYP3A1/2, and that 1,3-DMU is primarily formed via CYP1A1/2, and possibly CYP3A1/2, in rats.

Pharmacokinetics of L-FMAUS, a new antiviral agent, after intravenous and oral administration to rats: contribution of gastrointestinal first-pass effect to low bioavailability.

The pharmacokinetics of L-FMAUS after intravenous and oral administration (20, 50 and 100 mg/kg) to rats, gastrointestinal first-pass effect of L-FMAUS (50 mg/kg) in rats, in vitro stability of L-FMAUS, blood partition of L-FMAUS between plasma and blood cells of rat blood, and protein binding of L-FMAUS to 4% human serum albumin were evaluated. L-FMAUS is being evaluated in a preclinical study as a novel antiviral agent. Although the dose-normalized AUC values of L-FMAUS were not significantly different among the three doses after intravenous and oral administration, no trend was apparent between the dose and dose-normalized AUC. After oral administration of L-FMAUS (50 mg/kg), approximately 2.37% of the oral dose was not absorbed, and the extent of absolute oral bioavailability (F) was approximately 11.5%. The gastrointestinal first-pass effect was approximately 85% of the oral dose. The first-pass effects of L-FMAUS in the lung, heart and liver were almost negligible, if any, in rats. Hence, the small F of L-FMAUS in rats was mainly due to the considerable gastrointestinal first-pass effect. L-FMAUS was stable in rat gastric juices. The plasma-to-blood cells partition ratio of L-FMAUS was 2.17 in rat blood. The plasma protein binding of L-FMAUS in rats was 98.6%.

Effects of acute renal failure on the pharmacokinetics of telithromycin in rats: negligible effects of increase in CYP3A1 on the metabolism of telithromycin.

It was reported that the expression of CYP3A1 increased in rats with acute renal failure induced by uranyl nitrate (rat model of U-ARF) compared with controls. It was shown that telithromycin was mainly metabolized via CYP3A1/2 in rats in this study. Hence, the pharmacokinetic parameters of telithromycin were compared after both intravenous and oral administration at a dose of 50 mg/kg to control rats and a rat model of U-ARF. After intravenous administration of telithromycin to rats with U-ARF, the AUC and renal clearance (Cl(r)) were significantly greater (35.0% increase) and slower (99.1% decrease), respectively, than the controls. Unexpectedly, the nonrenal clearance (Cl(nr)) of telithromycin was comparable between the two groups of rats, suggesting that CYP3A isozyme responsible for the metabolism of telithromycin seemed not to be expressed considerably in the rat model of U-ARF. After oral administration of telithromycin to rats with U-ARF, the AUC was also significantly greater (127% increase) than the controls and the value, 127%, was considerably greater than 35.0% after intravenous administration of telithromycin. This may be due mainly to the decrease in the intestinal first-pass effect of telithromycin compared with controls in addition to significantly slower Cl(r) than controls.

Pharmacokinetics of oral amlodipine orotate in vagotomized dogs.

It was reported that gastric motility was delayed and gastric acid secretion was reduced in vagotomized dogs which mimics a low gastric acidity in humans. A delay in gastric motility causes long residence of amlodipine in the stomach. More unionized fractions of amlodipine could exist in less acidic conditions of gastrointestinal fluids, since amlodipine is a weak basic drug with pKa of 8.7. Hence, gastrointestinal absorption of amlodipine is expected to be enhanced and the time to reach a peak plasma concentration of amlodipine (Tmax) is faster in vagotomized dogs. This was proven after oral administration of an amlodipine orotate tablet at a dose of 5 mg as amlodipine in vagotomized dogs. For example, in vagotomized dogs, the total area under the plasma concentration-time curve from time zero to the last measured time, 48 h, in plasma (AUC(0-48 h)) was significantly greater (725 versus 348 ng h/ml) and Tmax was significantly shorter (1.50 versus 5.00 h) than those in dogs without vagotomy.