Iv Dose Research Articles

Identification of KD5170: A novel mercaptoketone-based histone deacetylase inhibitor

We report the identification of KD5170, a potent mercaptoketone-based Class I and II-histone deacetylase inhibitor that demonstrates broad spectrum cytotoxic activity against a range of human tumor-derived cell lines. KD5170 exhibits robust and sustained histone H3 hyperacetylation in HCT-116 xenograft tumors following single oral or iv dose and inhibition of tumor growth following chronic dosing.

Effects of Single IV Doses of BG9928, an Adenosine A1 Antagonist, in Patients with Heart Failure

Effects of Single IV Doses of BG9928, an Adenosine A1 Antagonist, in Patients with Heart Failure

Toxicokinetics of fumonisin B1 in turkey poults and tissue persistence after exposure to a diet containing the maximum European tolerance for fumonisins in avian feeds

The kinetic of fumonisin B1 (FB1) after a single IV and oral dose, and FB1 persistence in tissue were investigated in turkey poults by HPLC after purification of samples on columns. After IV administration (single-dose: 10 mg FB1/kg bw), serum concentration–time curves were best described by a three-compartment open model. Elimination half-life and mean residence time of FB1 were 85 and 52 min, respectively. After oral administration (single-dose: 100 mg FB1/kg bw) bioavailability was 3.2%; elimination half-life and mean residence time were 214 and 408 min, respectively. Clearance of FB1 was 7.6 and 7.5 ml/min/kg for IV and oral administration, respectively. Twenty-four hours after the administration of FB1 by the intravenous route, liver and kidney contained the highest levels of FB1 in tissues, level in muscle was low or below the limit of detection (LD, 13 μg/kg). The persistence of FB1 in tissue was also studied after administration for 9 weeks of a feed that contained 5, 10 and 20 mg FB1 + FB2/kg diet. Eight hours after the last intake of 20 mg FB1+FB2/kg feed (maximum recommended concentration of fumonisins established by the EU for avian feed), hepatic and renal FB1 concentrations were 119 and 22 μg/kg, level in muscles was below the LD.

Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc–Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice

c-Myc is commonly activated in many human tumors and is functionally important in cellular proliferation, differentiation, apoptosis and cell cycle progression. The activity of c-Myc requires noncovalent interaction with its client protein Max. In vitro studies indicate the thioxothiazolidinone, 10058-F4, inhibits c-Myc/Max dimerization. In this study, we report the efficacy, pharmacokinetics and metabolism of this novel protein-protein disruptor in mice. SCID mice bearing DU145 or PC-3 human prostate cancer xenografts were treated with either 20 or 30 mg/kg 10058-F4 on a qdx5 schedule for 2 weeks for efficacy studies. For pharmacokinetics and metabolism studies, mice bearing PC-3 or DU145 xenografts were treated with 20 mg/kg of 10058-F4 i.v. Plasma and tissues were collected 5-1440 min after dosing. The concentration of 10058-F4 in plasma and tissues was determined by HPLC, and metabolites were characterized by LC-MS/MS. Following a single iv dose, peak plasma 10058-F4 concentrations of approximately 300 muM were seen at 5 min and declined to below the detection limit at 360 min. Plasma concentration versus time data were best approximated by a two-compartment, open, linear model. The highest tissue concentrations of 10058-F4 were found in fat, lung, liver, and kidney. Peak tumor concentrations of 10058-F4 were at least tenfold lower than peak plasma concentrations. Eight metabolites of 10058-F4 were identified in plasma, liver, and kidney. The terminal half-life of 10058-F4 was approximately 1 h, and the volume of distribution was >200 ml/kg. No significant inhibition of tumor growth was seen after i.v. treatment of mice with either 20 or 30 mg/kg 10058-F4. The lack of significant antitumor activity of 10058-F4 in tumor-bearing mice may have resulted from its rapid metabolism and low concentration in tumors.

A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus docetaxel (D) and cisplatin (C) in patients (pts) with advanced solid tumors: preliminary results

14539 Background: Aflibercept (AF), a potent inhibitor of vascular endothelial growth factor, is a recombinant fusion molecule of the human VEGF receptor R1 + R2 (Flt-1, KDR) extracellular domains and the Fc portion of human IgG1. AF binds VEGF-A and neutralizes all VEGF-A isoforms plus placental growth factor. This study was designed to assess the safety, dose limiting toxicities (DLTs)/recommended dose (RD) and PK of AF + DC. Methods: This combination trial explored escalating iv doses of AF followed by fixed dose of D then C (each 75 mg/m2) every 3 weeks (q3w). Treatment cohorts consisted of at least 3 pts up to 6 pts in case of DLT. Results: 16 heavily pretreated pts (Male/Female 3/13, median age 55 [39–76], ECOG-PS 0/1: 9/7) were enrolled in 3 AF dose levels (4.0, 5.0 and 6.0 mg/kg). Pts’ cancers included breast (5), ovarian (5), colon (2) and others (4). Pts received a median number of 4 [2–8] treatment cycles (cy). DLTs were only hematological (febrile neutropenia at cy 1) for 1/6 pts at AF 4.0 mg/...

A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus weekly gemcitabine (Gem) in patients (pts) with advanced solid tumors: preliminary results

3558 Background: Aflibercept (AF) is a recombinant fusion protein that is a potent inhibitor of vascular endothelial growth factor (VEGF). This study was designed to assess the safety/tolerability, dose-limiting toxicities (DLTs), recommended Phase II dose, and PK of AF plus Gem. Methods: This combination trial explored escalating iv doses of AF, administered every 2 weeks(q2w), followed by standard weekly iv Gem (7w on/1w off, then 3w on/1w off every 4w). Results: 32 pts (M/F 9/23, median age 58 [38–75], ECOG-PS 0/1/2: 10/21/1) were enrolled in 2 AF dose levels: 4.0 (n = 20) and 6.0 (n = 12) mg/kg. Primary tumors included pancreas (11), breast (7), sarcoma (3), and others (11). Most (9/11) pancreatic pts were first-line. Other pts were heavily pre-treated, with a median of 3[1–11] prior lines. Pts received a median of 2 [1–9] 4w treatment cycles (cy). During the dose escalation phase, no AF-related DLT (first 4w cy) was observed. Gr > 3 NCI-CTCAE toxicities observed across doses included: neutropenia (34...

A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus FOLFOX4 in patients (pts) with advanced solid tumors: Preliminary results

3556 Background: Aflibercept (AF) is a recombinant fusion protein that is a potent inhibitor of vascular endothelial growth factor (VEGF). This study was designed to assess the safety/tolerability, dose-limiting toxicities (DLTs), recommended Phase II dose, and PK of AF + FOLFOX4. Methods: This combination trial explored escalating iv doses of AF followed by standard fixed FOLFOX4 regimen, every 2 weeks. Results: 32 pts (M/F 9/23, median age 59 [25–79], ECOG-PS 0/1: 11/21) were enrolled in 3 AF dose levels: 2.0 (n = 4), 4.0 (n = 18) and 5.0 (n = 10) mg/kg. Primary tumors were mostly gastro-intestinal (16, including 8 pancreas, 3 cholangiocarcinoma and 3 gastric), breast (5), ovarian (4), and others (7). Most (75%) pts were heavily pre-treated, with a median number of prior lines of 3[1–9]. Pts received a median number of 4.5 [1–20] treatment cycles (cy). During the dose escalation phase, no AF-related DLT (first 2 cy) was observed. Gr > 3 NCI-CTCAE v3.0 toxicity observed included: neutropenia (69%), thrombocytopenia (13%), hypertension (13%), proteinuria (13%), hemorrhagic events (9%, including one G5 hemorrhagic stroke at 4 mg/kg), febrile neutropenia (3%), deep vein thrombosis (3%). A G5 posterior leukoencephalopathy syndrome was reported at 5 mg/kg. Five partial responses were noted (pancreas, cholangiocarcinoma, colo-rectal; all at doses > 4 mg/kg) and 10 pts had stable disease. Free and bound AF drug concentrations in combination with FOLFOX4 are comparable to those observed with AF as monotherapy. At doses > 4 mg/kg, free AF exceeds bound AF over the dosing interval, suggesting sustained effective trapping of VEGF. Conclusions: AF 4 mg/kg combined with FOLFOX4 was selected for further investigations, based on activity, overall safety profile (consistent with that of other agents from the same class), and PK. Updated data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis

The timing of haloperidol administration does not affect its prophylactic antiemetic efficacy

Postoperative nausea and vomiting (PONV) occurs frequently after general anesthesia. We evaluated the timing of 2 mg iv doses of haloperidol on the efficacy of this drug as a prophylactic antiemetic for PONV. Ninety-four non-smoking female patients with a history of motion sickness and/or PONV (Apfel's simplified risk score=3; predicted incidence of PONV=60%) were eligible to participate in this randomized, double-blind study. Patients were divided into two groups. Group 1 patients received haloperidol 2 mg iv during induction of anesthesia. Group 2 patients received haloperidol 2 mg iv approximately 30 min before the end of surgery. The occurrence of nausea and vomiting, nausea scores, pain scores, sedation levels, and adverse effects (cardiac arrhythmias, and extrapyramidal effects) were recorded by a trained, blinded investigator. The percentages of patients who experienced PONV in the first 24 hr were similar for the two groups (Group 1=30%; Group 2=26%, P=0.645). The incidence of PONV was significantly smaller in both groups than that predicted (60%) according to the patients' underlying risks (Group 1, P=0.004; Group 2, P=0.001). Nausea scores, pain scores, sedation scores, emergence times, and time to first rescue treatment were similar in the two groups. No adverse effects attributable to the study medication were observed. The timing of administration of haloperidol 2 mg iv does not influence its antiemetic efficacy. The recovery profiles were also similar whether haloperidol was administered at the start, or at the end of surgery.

Protective effect of a novel soluble epoxide hydrolase inhibitor 1471 on brain damage after temporary MCAO in rats

Chemical inhibitors of soluble epoxide hydrolase and cytochrome P450 produce neuroprotection upon chronic dosing after focal ischemia. The purpose of this study was to determine the effects of a single dose of the 20‐HETE formation inhibitor (HET0016) or the soluble epoxide hydrolase inhibitor (1471) on lesion volume after focal ischemia. Male, Sprague‐dawley rats received single iv doses of vehicle, HET0016 (0.8 mg/kg), or 1471 (0.8 mg/kg) and were sacrificed at two hours for brain cortical HETE, EET, and DiHETrE measurement. In a separate study, each treatment was administered prior to insult and animals were sacrificed at 24 hours for lesion volume assessment. Our results show that 1471 decreased 14,15‐DiHETrE (controls: 1.89 ± 0.42pmol/gm vs 1471: 1.37 ± 0.51pmol/gm) and 11,12‐DiHETrE (controls: 0.61± 0.23 pmol/gm vs 1471: 0.31 ± 0.13pmol/gm) in the rat brain cortex with no significant alterations in HETE metabolites. Whereas, HET0016 reduced 20‐HETE (control 55.9±11.7pmol/gm vs HET0016 22.5±5.0pmol/gm) in the rat cortex without altering other HETEs or DiHETrEs (mean ±st dev; n=5). We also demonstrated that lesion volumes were significantly reduced after 1471dosing and were 15 ± 3% vs 42 ± 5 % (mean ± SEM; n=9) in vehicle control animals. Single dose administration of HET0016 did not alter lesion volume. These data demonstrate that 1471 is a potent neuroprotective agent after a single iv dose. Supported by NINDS R01NS052315 and NCRR S10RR023461.

Novel anti‐methamphetamine (METH) monoclonal antibodies (mAbs) substantially alter METH disposition and METH‐induced behavioral effects

We recently developed a novel series of anti‐METH mAbs against a METH‐like hapten. (designated MO10). MO10‐antigen immunization of mice resulted in two unique mAbs with high‐affinity binding to METH (mAb7F9, KD 1.8 nM), or METH (mAb4G9, KD 34 nM) and (+)amphetamine (AMP, KD 70 nM), with no cross‐reactivity against (−)isomers or endogenous neurotransmitters. The resulting mAbs were tested in rat pharmacokinetic and behavioral assays. For the pharmacokinetic studies, METH (5.6 mg/kg/day) was chronically administered via sc osmotic minipumps to male Sprague‐Dawley rats. At METH steady state, mAb was administered. Serum samples were collected for 2 wks. Both mAbs caused >60‐fold increases in METH serum concentrations compared to pre‐mAb levels, and increases were maintained throughout the study. mAb4G9 also significantly increased AMP serum levels. For behavioral studies, baseline locomotor effects of a 1 mg/kg METH iv dose were determined on day 1 and 4. On day 7, mAb was given 30 min after METH. mAb4G9 caused 54% and 55% reductions in distance traveled and rearing, while mAb7F9 resulted in 48% and 64% reductions, respectively. These data show that anti‐METH mAbs effectively alter METH pharmacokinetic and behavioral effects in preclinical models of human METH abuse (Supported by NIDA P01 DA14361 and R01DA11560).

Clinical Efficacy of Bortezomib Based Therapy in Plasma Cell Leukemias.

Introduction Plasma Cell Leukemia (PCL) is characterized by a high number of plasma cells in peripheral blood (>2 × 109/L) and more than 20% of circulating plasmocytes on differential count. Primary PCL or secondary form, after previous multiple myeloma (MM), represent the most aggressive forms of clonal gammapathy with very poor outcome from both conventional chemotherapy and autologous or allogeneic transplant. For this reasons new effective treatment approaches are required. The proteasome inhibitor Bortezomib has been shown to be effective in advanced MM with a rapid response but few reports have been published regarding its potential role on PCL. We report here the clinical results of a serie of PCL patients that received proteasome inhibitor, Bortezomib (Velcade®), as induction therapy.Patients and Clinical Results We describe 10 patients with PCL treated with Bortezomib. Median age was 58 y (30–70). 4 cases were primary, de novoPCL and 6 cases were secondary forms of relapsed or progressive MM. Patients with secondary PCL had received a median of 3 previous lines of therapy including autologous transplantation (5 cases). Bortezomib at standard dose iv: 1.3 mg/m2 days 1,4, 8,11 every 21 days were used alone in 2 patients and in combination with high dose of Dexamethasone +/− Adryamicin in the rest. 3 cases recived the BDD scheme (Bortezomib iv, Pegylated Doxorrubicin iv and oral Dexamethasone). 9 patients were evaluable for drug efficacy with 7 cases showing some grade of favourable response with the first cycle, including 3 cases of CR. 4 patients have died: 1 during first weeks and 3 for progression, 2–3 months after initial response. 3 cases received allogeneic transplant with related donor and reduced conditioning and are alive 12, 14 and 30 months postransplant. The median follow up since PCL diagnosis of 6 alive patients is 14 months (3–39 months). 3 patients received maintenance therapy that included low dose thalidomide. Grade 2 thrombopenia, neutropenia and gastrointestinal symptoms were the main secondary toxicity. No complicated tumoral lysis syndrome were observed.Conclusions and Comments Bortezomib has been shown to be effective by several mechanisms in patients with MM resistant to multiple previous treatments and as induction therapy alone or in combination with other drugs. The favourable responses observed in these cases of PCL; including de novo patients, and the biological ex vivo results in PCL cell lines, suggest the potential efficacy of this agent combined with dexamethasone and doxorubicin. Although more experience is necessary these data support future trials with Bortezomib combined with other drugs for example BDD scheme in the induction treatment of PCL. The role of allogeneic intensification therapy has also to be investigated in young patients after control of PCL with this approach. For maintenance of response, the role of this drug or other new drugs as thalidomide or lenalidomide has to be investigated.

Oral bioavailability, tissue distribution and depletion of flumequine in the food producing animal, chicken for fattening

Chickens were used to investigate kinetic properties including metabolism of flumequine after single IV and oral dose, and to study tissue depletion of flumequine after multiple oral doses. Plasma and tissue (muscle, kidney, liver and skin plus fat) concentrations of flumequine and its metabolite 7-hydroxyflumequine were determined using a HPLC method. After IV and oral administration (single-dose of 12 mg flumequine/kg bw), plasma concentration–time curves were best described by a two-compartment open model. Elimination half-life and mean residence time of flumequine in plasma were 6.91 and 5.90 h, respectively, after IV administration and 10.32 and 8.95 h after oral administration. Maximum plasma concentration was 3.62 μg/ml and interval from oral administration until maximum concentration was 1.43 h. Oral bioavailability was found to be 57%. Flumequine was converted to 7-hydroxyflumequine. After oral administration (24 mg/kg bw every 24 h for 5 days), renal and hepatic concentrations of flumequine (18–25 μg/kg) persisted for 4 days; however, at that time, flumequine residues were not detected in skin plus fat and muscle tissues. Flumequine administered at a dosage of 24 mg/kg bw every 24 h for 5 days, with a withdrawal time of 2 days, resulted in flumequine concentrations in target tissues that were less than the European Union maximal residue limits.

The National Epirubicin Adjuvant Trial (NEAT) and Scottish Cancer Trials Breast Group (SCTBG) br9601 randomized phase III adjuvant early breast cancer trials: The updated definitive joint analysis

534 Background: NEAT and the SCTBG BR9601 trial address the role of Epirubicin (E) as an adjunct to CMF in adjuvant chemotherapy for women with early breast cancer (EBC). Methods: NEAT compared E (100mg/m2 x4cycles) followed by classical (c)CMF (x4cycles) with cCMF (x6cycles); BR9601 compared E (100mg/m2 × 4cycles) followed by iv dose modified CMF q3w (750:50:600 ×4cycles) with iv CMF (x8cycles). Eligibility was completely excised EBC, requiring adjuvant chemotherapy, and start of treatment <10 wks from surgery. Primary outcome measures were relapse-free-survival (RFS) and overall survival (OS). A joint efficacy analysis of NEAT (n=2,021) and BR9601 (n=370) triggered by planned 5-year median follow-up (FU) and estimated 800 RFS events and 600 deaths has 85% power to detect 5% two-sided differences. Results: In 2,391 eligible patients, characteristics were balanced across treatments: 72% node +ve; 59% <50 years old; 47% pre-menopausal; 58% tumours grade 3; 55% >2cms; 32% ER-ve, 50% ER+ve (18% NA). At a median FU of 6.2 yrs, 710 relapses or deaths without relapse and 570 deaths are observed. Despite lower than anticipated event rates in the control arm, these updated results confirm a highly significant benefit in favour of ECMF for both RFS (HR 0.75 (95%CI 0.64–0.87) p=0.0002) and OS (HR 0.74 (0.62–0.87) p=0.0004), independent of trial and prognostic factors. In 1458 NEAT patients (in whom data are available), 68% were to receive tamoxifen; chemotherapy scheduling data is available for 843, of whom 46% were declared concurrent and 54% sequential. In a non-pre-planned retrospective analysis, sequential tamoxifen shows a trend for advantage on RFS (HR 0.78 (0.59–1.02) p=0.06). We have amenorrhoea data on 598 NEAT and BR9601 pre-menopausal women, of whom 72% became amenorrhoeic by the end of chemotherapy. In this instance, developing amenorrhoea showed no advantage for RFS (HR 0.90 (0.65–1.24) or OS (HR 0.99 (0.68–1.44)). Conclusions: This updated definitive analysis adds to the Overview in respect of an anthracycline advantage and confirms ECMF as an established and effective standard adjuvant therapy for EBC. [Table: see text]

Survival and long-term toxicities of biochemotherapy for metastatic melanoma

8553 Purpose: Because long-term survival after therapy for advanced stage IV melanoma is rare, we thought it would be useful to examine our series of survivors treated with biochemotherapy for melanoma to analyze the characteristics of survivors and their chronic toxicities. Patients and Methods: We reviewed our previously reported (J Clin Oncol. 2005:23:16s suppl, abstract 7547) consecutive series of 38 patients treated between 9/02 and 7/04. They received 6 cycles of inpatient temozolomide, cisplatin, vinblastine, decrescendo high- dose iv IL-2 , and interferon followed by maintenance immunotherapy using IL-2 and sargramostim using the O’Day regimen (Clinical Cancer Res. 2002:8:2775).Two of the ten long-term survivors received surgery for resection of residual disease after achieving a partial response with biochemotherapy. Maintenance immunotherapy was given for 6 to 24 months after biochemotherapy. Results: The median progression- free survival was 7.3 months. No patient developed progression later than 17 months after the start of therapy with the progression-free survival curve level at 24%. Median overall survival was 16.2 months. 10 of the 38 patients are alive and disease-free off therapy after an average of 3.3 years follow-up. Durable complete responses were seen in visceral sites including lung, bone, and pericardium, with 8 of 10 long- term survivors having M1B or M1C disease. 3 patients have significant lymphedema related to prior surgery, radiation therapy, or both. 2 patients, one with pre-existing diabetes, have significant persisting neuropathy. 5 of the 10 patients are hypothyroid. Menstrual function returned in the three women under age 45 in this study. Conclusion: This series supports the findings from other series that biochemotherapy, like high-dose IL-2, can give prolonged disease-free survival. Survivors have a high incidence of hypothyroidism but neuropathy and lymphedema, which affected a minority of patients, were the most bothersome long-term toxicities. No significant financial relationships to disclose.

Persistent Tissue Kinetics and Redistribution of Nanoparticles, Quantum Dot 705, in Mice: ICP-MS Quantitative Assessment

BackgroundQuantum dots (QDs) are autofluorescent semiconductor nanocrystals that can be used for in vivo biomedical imaging. However, we know little about their in vivo disposition and health consequences.ObjectivesWe assessed the tissue disposition and pharmacokinetics of QD705 in mice.MethodsWe determined quantitatively the blood and tissue kinetics of QD705 in mice after single intravenous (iv) injection at the dose of 40 pmol for up to 28 days. Inductively coupled plasma–mass spectrometry (ICP-MS) measurement of cadmium was the primary method of quantification of QD705. Fluorescence light microscopy revealed the localization of QD705 in tissues.ResultsPlasma half-life of QD705 in mice was short (18.5 hr), but ICP-MS analyses revealed QD705 persisted and even continued to increase in the spleen, liver, and kidney 28 days after an iv dose. Considerable time-dependent redistribution from body mass to liver and kidney was apparent between 1 and 28 days postdosing. The recoveries at both time points were near 100%; all QD705s reside in the body. Neither fecal nor urinary excretion of QD705 was detected appreciably in 28 days postdosing. Fluorescence microscopy demonstrated deposition of QD705 in the liver, spleen, and kidneys.ConclusionJudging from the continued increase in the liver (29–42% of the administered dose), kidney (1.5–9.2%), and spleen (4.8–5.2%) between 1 and 28 days without any appreciable excretion, QD705 has a very long half-life, potentially weeks or even months, in the body and its health consequences deserve serious consideration.

Disposition of [14C]N,N-Dimethyl-p-Toluidine in F344 Rats and B6C3F1 Mice

N,N-Dimethyl-p-toluidine (DMPT) is used as a polymerization accelerator, in industrial glues, and as an intermediate in dye and pesticide synthesis. There is potential for human exposure to DMPT. The disposition of oral and intravenous (iv) doses of [14C]DMPT in F344 rats and B6C3F1 mice was investigated. A single iv (2.5 mg/kg) or oral (2.5, 25, or 250 mg/kg) dose of [14C]DMPT (1–25 μCi) was administered in an aqueous vehicle to male rats and mice. The 25-mg/kg oral dose was administered to females to investigate possible gender differences in disposition. However, no striking gender differences were observed. Since toxicity studies conducted elsewhere used a corn oil vehicle, the 250-mg/kg oral dose also was administered in corn oil to male rats; disposition was not dependent on vehicle. Excreta (through 24 h) and tissues collected at sacrifice were analyzed for total radioactivity. Dose-dependent differences in toxicity and disposition were observed. Toxicity at the 250-mg/kg oral dose to male mice was consistent with acute renal failure. At the same dose, male rats exhibited clinical signs of toxicity through 12 h but were clinically normal by 24 h. At lower oral doses, [14C]DMPT-derived radioactivity was well absorbed and rapidly excreted, primarily in urine.

Formulation-dependent toxicokinetics explains differences in the GI absorption, bioavailability and acute neurotoxicity of deltamethrin in rats

The acute neurotoxicity of pyrethroid insecticides varies markedly with the dosage vehicle employed. The objective of the present study was to assess the influence of two common vehicles on the bioavailability and toxicokinetics (TK) of a representative pyrethroid insecticide, deltamethrin (DLM), to determine whether the vehicles influence toxic potency by modifying the chemical's TK. Adult, male Sprague–Dawley rats were administered DLM iv or po, either by dissolving it in glycerol formal (GF) or by suspending it in Alkamuls ® (AL). Groups of rats received 10 mg DLM/kg by gavage in each vehicle, as well as 2 mg/kg in GF or 10 mg/kg in AL by iv injection. Serial blood samples were collected over 96 h and analyzed for their DLM content by HPLC. In a second experiment, plasma, brain, fat, liver and lung DLM concentrations were measured 2 h after giving 10 mg DLM/kg orally in GF or AL. In a third experiment rats received 2 or 10 mg DLM/kg iv in AL or 2 mg DLM/kg iv in GF. Lung DLM content was determined 15 min post injection. DLM particle size in both formulations was measured under a phase contrast microscope. DLM appeared to be completely dissolved in GF, while particle size ranged from <5 to >50 μm in AL. The bioavailability of DLM in the aqueous AL suspension was ∼9-fold lower than in GF (1.7% versus 15%). Blood C max (0.95 ± 0.27 versus 0.09 ± 0.01 μg/ml) and AUC 0 48h (5.49 ± 0.22 versus 0.61 ± 0.14 μg·h/ml) were markedly higher in the GF gavage group. Tissue DLM levels were also significantly higher in the GF animals at 2 h. The 10 mg/kg po and 2 mg/kg iv doses of DLM in GF produced moderate salivation and slight tremors. Rats receiving the insecticide in AL were asymptomatic. IV injection of the AL suspension resulted in trapping of much of the dose in the pulmonary capillaries. As anticipated, the injected suspension had a longer half-life and slower clearance than did the GF formulation. In summary, limited dissolution of the highly lipophilic DLM particles in the AL suspension severely limited DLM's GI absorption, bioavailability, target organ deposition and acute neurotoxic potency.

Brain Uptake, Pharmacokinetics, and Tissue Distribution in the Rat of Neurotoxic N-Butylbenzenesulfonamide

The pharmacokinetics, cerebrovascular permeability, and tissue distribution of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS) were determined in rats. A stable isotope-labeled form ([(13)C(6)]NBBS) was used to circumvent ubiquitous contamination that was evident whenever the native form was measured. Plasticizer decline in plasma, following an iv dose of 1 mg/kg, was described by a triexponential decay function. NBBS was cleared from plasma at a rate of 25 ml/min/kg, and 24 h after administration, plasma concentrations represented 0.04% of the administered dose. These data suggest rapid elimination and uptake into tissue; however, NBBS was not accumulated by any of the tissues studied (i.e., liver, kidney, muscle, adipose tissue, and brain). Given the critical interest in NBBS neurotoxicity, the brain uptake of [(13)C(6)]NBBS was further explored in experiments using the in situ brain perfusion technique. During perfusion with protein-free saline for 15-30 s, the single-pass brain extraction for free [(13)C(6)]NBBS was very high (73-100%) with a unidirectional blood-brain barrier transfer constant (K(in)) of > 0.08 ml/s/g. No significant differences were found in [(13)C(6)]NBBS content among the measured brain regions. Plasma protein binding (70%) only slightly lowered the single-pass brain extraction to 48%. In summary, the results demonstrate that NBBS distributes rapidly to tissues, including brain. Though highly lipophilic with a Log octanol/water partition coefficient of 2.17 +/- 0.09, brain:blood ratios (2:1) for NBBS were consistent throughout the experimental duration, with little indication of accumulation.

Pharmacokinetic behaviors and oral bioavailability of oridonin in rat plasma

To study the intravenous and oral pharmacokinetic behavior of oridonin and its extent of absolute oral bioavailability in rats. Oridonin was administered to rats via iv (5, 10 and 15 mg/kg), po (20, 40 and 80 mg/kg) or ip administration (10 mg/kg). The concentrations of oridonin in rat plasma were determined by a high performance liquid chromatography with electrospray ionization mass spectrometric detection (HPLC/ESI-MS) method and the pharmacokinetic parameters were determined by non-compartmental analysis. The plasma concentration of oridonin after intravenous administration decreased polyexponentially, and the pharmacokinetic parameters of oridonin were dose-independent within the examined range. Oridonin was absorbed rapidly after oral gavage with a t(max) of less than 15 min; the extent of absolute bioavailability of oridonin following oral administration was 4.32%, 4.58% and 10.8%. The extent of absolute bioavailability of oridonin following intraperitoneal administration was 12.6%. First order rate pharmacokinetics were observed for oridonin within the range of iv doses, while the extent of absolute oral bioavailability was rather low and dose- dependent. The low and dose-dependent extent of oral bioavailability may be due to the saturation of first-pass effects.

Penetration of moxifloxacin into the human pancreas following a single intravenous or oral dose

Failure to prevent secondary infectious complications in acute necrotizing pancreatitis (ANP) is attributable in part to the limited penetration of antimicrobial drugs. As newer quinolones are particularly attractive owing to their antimicrobial activity, for the first time we studied the penetration of moxifloxacin into pancreatic tissue in patients. In this prospective, non-comparative clinical trial, 60 patients undergoing elective pancreas resection received a single oral or intravenous (iv) dose of 400 mg moxifloxacin for perioperative antimicrobial prophylaxis. The concentration of moxifloxacin was measured in samples taken from blood and from pancreatic tissue at the beginning and at the end of resection. Mean moxifloxacin concentrations in pancreatic tissue following iv or oral administration were 3.1+/-0.9 and 2.7+/-1.4 mg/kg at 3-3.7 h post-dose (first sampling) and 3.6+/-1.5 and 3.1+/-1.8 mg/kg at 4.3-5.3 h post-dose (second sampling), respectively. Corresponding mean plasma concentrations of moxifloxacin were 1.8+/-0.5 and 1.2+/-0.6 mg/L (first sampling) and 1.5+/-0.4 and 1.0+/-0.5 mg/L (second sampling), respectively. From first to second sampling, the mean tissue-to-plasma ratios varied from 1.8+/-0.6 to 2.6+/-1.2 (iv) and from 2.4+/-0.8 to 3.1+/-1.2 (oral). Pancreatic tissue concentrations of moxifloxacin exceeded the MIC90 for the relevant pathogens covered by moxifloxacin for at least 5 h after dosing. Moxifloxacin has been demonstrated to penetrate efficiently into human pancreatic tissue following iv or oral administration. From a pharmacological perspective, moxifloxacin appears to be promising for prophylaxis and treatment of local pancreas infections. Whether it is beneficial in the prevention and therapy of infectious complications in patients with ANP should be investigated in a controlled clinical trial.