Genome-wide analysis of differentially expressed lncRNA in sporadic parathyroid tumors.

Diagnosis of parathyroid carcinoma on histological examination is challenging. Thousands of differentially expressed lncRNAs were identified on the microarray data between parathyroid cancer and adenoma samples. Four lncRNAs were significantly dysregulated in further validation. The "lncRNA score" calculated from these lncRNAs differentiated parathyroid carcinomas from adenomas. LncRNAs serve as biomarkers for parathyroid cancer diagnosis. INTRODUCTION: Diagnosis of parathyroid carcinoma (PC) on histological examination is challenging. LncRNA profile study was conducted to find diagnostic biomarkers for PC. METHODS: LncRNA arrays containing 91,007 lncRNAs as well as 29,857 mRNAs were used to assess parathyroid specimen (5 carcinomas and 6 adenomas). Bioinformatics analyses were also conducted to compare the microarray results between parathyroid carcinomas and adenomas (PAs). Differentially expressed lncRNAs of 11 PCs and 31 PAs were validated by real-time quantitative PCR. RESULTS: On the microarray data between PC and PA samples (fold change ≥ 2, P < 0.05), 1809 differentially expressed lncRNAs and 1349 mRNAs also were identified. All carcinomas were clustered in the same group by clustering analysis using dysregulated lncRNAs or mRNAs. Four lncRNAs (LINC00959, lnc-FLT3-2:2, lnc-FEZF2-9:2, and lnc-RP11-1035H13.3.1-2:1) identified were significantly dysregulated in further RT-PCR validation. The global "lncRNA score" calculated from the lncRNAs above also differentiated parathyroid carcinomas from adenomas. CONCLUSIONS: LncRNA profiling shows distinct differentially expressed lncRNAs in parathyroid neoplasm. They may play a key role in parathyroid cancer and serve as potential biomarkers to distinguish parathyroid cancers from parathyroid adenomas.

Predictors of survival after resection of children with hepatoblastoma: A single Asian center experience.

AIM: The aim of this study is to investigate and identify the predictors associated with the prognosis of patients with hepatoblastoma (HB). METHODS: We retrospectively reviewed 112 children with HB (58 female, 54 male) managed in our institution between May 1st, 2001 and January 30th, 2012. Prognostic factors were evaluated using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: For the entire cohort of 112 patients, the overall median survival was 83.5 months, and the 5-year EFS and OS rates were 57.1% and 63.4%, AFP<100 or >1000 (ng/ml)(HR:2.454, P = 0.013), multifocality (HR:2.852, P = 0.012), vascular invasion (HR:2.272, P = 0.026), metastases (HR:2.654,P = 0.005) and PRETEXT stage (HR:2.817, P = 0.005) were associated with an adverse prognosis in the univariate and multivariable adjusted analysis. Based on these findings, a prognostic scoring system was developed that allotted one point each for these factors. Patients with HB could be stratified into 3 distinct prognostic groups (median and 5-year EFS, respectively): 0 points (105.1 months, 94.1%), 1-2 point (85.8 months, 60.2%), and 3-4 points (31.8 months, 13.5%) (P < 0.001). CONCLUSIONS: We have confirmed the HB prognostic factors associated with survival in the Asian population and established a simple prognostic scoring system.

Is resectable hepatocellular carcinoma a contraindication to liver transplantation? A novel decision model based on "number of patients needed to transplant" as measure of transplant benefit.

BACKGROUND & AIMS: Number-needed-to-treat is used in assessing the effectiveness of a health-care intervention, and reports the number of patients who need to be treated to prevent one additional bad outcome. Although largely used in medical literature, there are no studies measuring the benefit of liver transplantation (LT) over hepatic resection (HR) for hepatocellular carcinoma (HCC) in terms of "Number of patients needed to transplant (NTT)." EXCLUSION CRITERIA: Child-Turcotte-Pugh (CTP) Classes B-C, very large (>10 cm) and multi-nodular (>2 nodules) tumours, macroscopic vascular invasion and extra-hepatic metastases. STUDY POPULATION: 1028 HCC cirrhotic patients from one Eastern (n=441) and two Western (n=587) surgical units. Patient survival observed after HR by proportional hazard regression model was compared to that predicted after LT by the Metroticket calculator. The benefit obtainable from LT compared to resection was analysed in relationship with number of nodules (modelled as ordinal variable: single vs. oligonodular), size of largest nodule (modelled as a continuous variable), presence of microscopic vascular invasion (MVI), and time horizon from surgery (5-year vs. 10-year). RESULTS: 330 patients were beyond the Milan criteria (32%) and 597 (58%) had MVI. The prevalence of MVI was 52% in patients within Milan criteria and 71% in those beyond (p<0.0001). In the 5-year transplant benefit analysis, nodule size and HCC number were positive predictors of transplant benefit, while MVI had a strong negative impact on NTT. Transplantation performed as an effective therapy (NTT <5) only in oligonodular HCC with largest diameter >3cm (beyond conventional LT criteria) when MVI was absent. The 10-year scenario increased drastically the transplant benefit in all subgroups of resectable patients, and LT became an effective therapy (NTT <5) for all patients without MVI whenever tumor extension and for oligonodular HCC with MVI within conventional LT criteria. CONCLUSIONS: Based on NTT analysis, the adopted time horizon (5-year vs. 10-year scenario) is the main factor influencing the benefit of LT in patients with resectable HCC and Child A cirrhosis.

Systemic uptake and cutaneous disposition of pentachlorophenol in a sequential exposure scenario: effects of skin preexposure to benzo[a]pyrene.

Characterizing interactions caused by sequential skin exposures to various environmental toxicants can be critical for a meaningful risk assessment. To assess sequential chemical exposure effect on chemical cutaneous disposition and systemic uptake of a toxicant, [(14)C]pentachlorophenol (PCP) was topically administered in three porcine skin models (in vivo, ex vivo, and in vitro) at 40 micro g/cm(2) with or without skin preexposure to benzo[a]pyrene (BaP), a known human carcinogen and cutaneous cytochrome P-450 (CYP450) inducer. In the mass balance studies, BaP skin preexposure was found to enhance (14)C absorption in all three models with detectable in vivo effect during the first several days. Total 8-h absorption was tripled by skin preexposure to BaP in the ex vivo (1.1 to 3.2%) and in vitro (0.20 to 0.66%) systems. As seen in the extended in vivo studies, total absorption was 50-57% regardless of exposure conditions, suggesting the prolonged observation period may conceal existing impact of potentially modified disposition processes, such as cutaneous metabolism, on systemic absorption. Skin preexposure to the skin CYP450 inducer BaP largely changed label penetration depth and distribution pattern in cutaneous tissues and decreased (14)C concentration in skin and fat. Additionally, BaP preexposure altered (14)C systemic tissue disposition, suggesting that altered cutaneous PCP disposition may eventually change the toxicity profile (cutaneous vs. systemic risk). The preliminary tissue distribution and systemic absorption data suggested that skin preexposure to BaP may considerably modify cutaneous biotransformation rate and thus deserves further investigation. The dermal model-dependent impacts of expected skin biotransformation manipulation by preexposure to chemicals such as BaP on cutaneous disposition and systemic uptake of environmental toxicants such as PCP need to be considered in risk assessment.

Enhanced systemic tissue distribution after dermal versus intravenous 3,3',4,4'-tetrachlorobiphenyl exposure: limited utility of radiolabel blood area under the curve and excretion data in dermal absorption calculations and tissue exposure assessment.

As a dioxin-like polychlorinated biphenyl (PCB), 3,3',4,4'-tetrachlorobiphenyl (TCB) is receiving increasing research and regulatory interest due to its high toxicity and persistence in the environment. (14)C-TCB was administered at an identical dose of 300 microg via the intravenous (iv) or dermal route to swine to examine the exposure route dependency of the relationship between tissue exposure and blood area under the curve (AUC) and the relationship between dermal absorption and excretion of radiolabel. After iv and dermal exposure, blood, urine, and feces samples were collected during the 11-day in vivo studies. At the end of the experiments, full mass balance studies were conducted to characterize tissue distribution of label. On average, over 70% of the applied dermal and iv doses were recovered. As expected, more than a 10-fold increase in blood AUC (0.49 vs 0.031, h x % dose/ml), plasma AUC (0.40 vs 0.038, h x % dose/ml), urine excretion (29 vs 2.3% of the applied dose), and fecal (30 vs 3.0% of the applied dose) excretion was determined after iv exposure compared to dermal exposure. However, we unexpectedly found that the tissue residue following iv exposure (8.0% of the applied dose) was only half that following dermal exposure (16% of the applied dose). Significantly larger (20- to 30-fold) ratios of blood AUC:tissue residue and excretion:tissue residue were observed after iv exposure compared to dermal exposure. This may indicate a route-related concentration-dependent blood-to-tissue partition process of pooled label, unique skin metabolism, or saturable hepatic metabolism of TCB. Thus, a long-term, low-input exposure pattern similar to this dermal exposure could be more harmful to systemic tissues than a short-term, high-dose exposure similar to this iv exposure. One should be aware that greater absorption, higher blood concentrations, greater blood and plasma AUCs, and greater excretion of label do not necessarily result in a greater overall tissue exposure and that some conventional approaches using label determination in blood and excreta without full mass balance studies may underestimate dermal absorption of chemicals similar to TCB.

Pharmacokinetics of sarafloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications.

Pharmacokinetics of sarafloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of 5 (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analysed by a noncompartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2beta) were 3.37 +/- 0.46, 4.66 +/- 1.34, 7.20 +/- 1.92 (pigs) and 2.53 +/- 0.82, 6.81 +/- 2.04, 3.89 +/- 1.19 h (broilers), respectively. After i.m. and p.o. doses, bioavailabilities (F) were 81.8 +/- 9.8 and 42.6 +/- 8.2% (pigs) and 72.1 +/- 8.1 and 59.6 +/- 13.8% (broilers), respectively. Steady-state distribution volumes (Vd(ss)) of 1.92 +/- 0.27 and 3.40 +/- 1.26 L/kg and total body clearances (ClB) of 0.51 +/- 0.03 and 1.20 +/- 0.20 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), mean residence times (MRT), and mean absorption times (MAT) were also determined. Sarafloxacin was demonstrated to be more rapidly absorbed, more extensively distributed, and more quickly eliminated in broilers than in pigs. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 10 mg/kg given intramuscularly every 12 h in pigs, or administered orally every 8 h in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 microg/mL.

Dermatoxicokinetic modeling of p-nitrophenol and its conjugation metabolite in swine following topical and intravenous administration.

The development of a dermatotoxicokinetic (dTK) model for p-nitrophenol (PNP), a common metabolite from a variety of compounds and a biomarker of organophosphate (OP) insecticide exposure, may facilitate the kinetic modeling and risk assessment strategy for its parent compounds. In order to quantify and then clarify in vivo-in vitro correlation of PNP disposition, multicompartment kinetic models were formulated. Female weanling pigs were dosed with [14C]PNP intravenously (150 microg in ethanol, n = 4) or topically onto non-occluded abdominal skin (300 microg/7.5cm2 in ethanol, n = 4). PNP and p-nitrophenyl-beta-D-glucuronide (PNP-G) profiles were determined in plasma and urine in addition to total 14C quantitation in many other samples. Disposition parameters (rate constants, Ftop, T12, T1/2Ka, AUC, Vss, Clp, MAT, and MRT) and the simulated chemical mass-time profiles on the dosed skin surface and in the local, systemic, and excretory compartments were also determined. Total recoveries of 97.17 +/- 4.18% and 99.80 +/- 2.41% were obtained from topical and intravenous experiments, respectively. Ninety-six hours after topical and intravenous application, 70.92 +/- 9.72% and 98.65 +/- 2.43% of the dose were excreted via urine, and 0.55 +/- 0.16% and 0.51 +/- 0.10% via the fecal route, respectively. Peak excretion rate and time were also determined. It was suggested by experimental observation and modeling that urinary 14C excretion correlates with the systemic tissue depletion profile well and may be used as a biomarker of PNP exposure. This study also supports the strategy of using urinary PNP as a biomonitoring tool for OP pesticide exposure, although some precautions have to be taken. The strategy used in this study will be useful in comprehensive dTK modeling in dermal risk assessment and transdermal drug delivery.

[The development of mouse bioreactor expressing human tissue plasminogen activator (tPA) in mammary gland by transfecting spermatozoa in testicular duct].

The most established methods for development of transgenic animals are the microinjection of DNA into the fertilized eggs, but it is still a procedure of certain complexity and high cost. Therefore, the idea of using sperm as a vehicle to carry exogenous DNA into eggs is very attractive, and there have been some successful reports. Though the methods are rather simple they sometimes have low reproducibility. To improve the technique we transinfected the spermatozoa in testicular duct, not in vitro, to produce mice which expressed human tissue plasminogen activator (tPA) in mammary gland. The results demonstrated that: (1) 5 transinfected mice mated 10 female mice in 10 days after operation, (2) 79 founders were developed and 42 survived, (3) using PCR to detect foreign DNA integrated into the genome of founders, 7 out of 42 founders were positive (16.67%), (4) The expression level of tPA was 48-80 ng/ml in the milk of 5 PCR positive founders and (5) the foreign DNA integrated into the genome was detected in 2 out of 4 1st offspring by PCR technique.

Cutaneous toxicity of the benzidine dye direct red 28 applied as mechanistically-defined chemical mixtures (MDCM) in perfused porcine skin.

Complex chemical mixtures at hazardous waste sites can potentially consist of a marker chemical and several other chemicals, each of which can have different modulating actions on the dermatotoxicity of the marker chemical and/or other components in the mixture. A total of 16 mixtures, consisting of a marker chemical direct red 28 (DR28), a solvent (80% acetone or DMSO in water), a surfactant (0 or 10% sodium lauryl sulfate, SLS), a vasodilator (0 or 180 microg methyl nicotinate, MN) and a reducing agent (0 or 2% stannous chloride, SnCl2) were selected. Isolated perfused porcine skin flaps (IPPSFs), which have been proven to be an in vitro model for assessing absorption and toxicity, were utilized. These mixtures did not cause severe dermatotoxicity. However, light microscopic observations depicted minor alterations (intracellular and intercellular epidermal edema) with DMSO mixtures than with acetone mixtures. The presence of SLS caused an alteration in the stratum corneum. Enzyme histochemical staining for alkaline phosphatase (ALP) and nonspecific esterase (NSE) revealed no significant treatment effects, but increased staining for acid phosphatase (ACP) in the stratum basale was significant when associated with SLS or SLS + MN in DMSO mixtures. At 8 h post-dose, only DMSO mixtures containing SL + MN, SL + SnCl2, or SLS + MN + SnCl2 significantly increased transepidermal water loss. In conclusion, this study demonstrated that various mixtures, especially those containing SLS alter the epidermal barrier differently with complex interactions occurring simultaneously.

Pentachlorophenol dermal absorption and disposition from soil in swine: effects of occlusion and skin microorganism inhibition.

Residue of the environmentally relevant biocide pentachlorophenol (PCP) is found mainly in soil, making dermal contact one of the primary routes for PCP exposure. To quantify exposure effects on dermal absorption and systemic disposition, [14C-UL]PCP was dosed nonocclusively or occlusively at 40 micrograms/cm2 in a soil-based mixture in an in vivo swine model. Additionally, antibiotics were also codosed with occlusive PCP in soil to examine the impacts of skin microbial PCP biodegradation on total dermal absorption. Under nonocclusive, occlusive, and occlusive-antibiotic conditions, total radiolabel absorption by 408 hr was 29.08, 100.72, and 86.21% dose, respectively. Tissue accumulation of PCP and its labeled metabolite(s) was very significant in swine since one-half to two-thirds of the absorbed dose was still present in tissues by 17 days after PCP dermal exposure. High 14C concentrations were found in liver, kidney, lung, ovary, and uterus. Urine and fecal routes were equally important for label excretion from the body. Occlusion enhanced total dermal absorption and changed the shape of the absorption profiles in the blood and plasma. Skin microorganism inhibition retarded 14C dermal absorption, altered local and systemic tissue distribution, and increased plasma/blood concentration ratios, suggesting skin microbial PCP degradation might play an important role in the altered absorption and disposition by occlusion. This study demonstrated significant dermal absorption and extensive tissue persistence of PCP after soil exposure. Occlusion and skin microflora growth may greatly impact dermal absorption, cutaneous disposition, and systemic toxic input. Therefore, exposure-specific PCP absorption and disposition profiles must be taken into consideration in risk analysis.

The use of mechanistically defined chemical mixtures (MDCM) to assess component effects on the percutaneous absorption and cutaneous disposition of topically exposed chemicals. I. Studies with parathion mixtures in isolated perfused porcine skin.

Recently, attention has been directed to the risk assessment of cutaneous exposure to chemical mixtures rather than to only a single compound since this is the exposure scenario in the environment, residence, and work place. Using acetone or dimethylsulfoxide (DMSO) (80% in water) as a vehicle, percutaneous absorption and cutaneous disposition of parathion (PA) were studied following PA (40 microg/cm2) dosing on isolated perfused porcine skin as mechanistically defined chemical mixtures (MDCM) consisting of the surfactant sodium lauryl sulfate (SLS), the rubefacient methyl nicotinate (MNA), and the reducing agent stannous chloride (SnCl2). A full 2 x 4 factorial design was used to asses treatment effects and potential interactions. More radiolabel was absorbed with DMSO than with acetone albeit an earlier peak flux time but lower peak flux was observed with acetone than with DMSO. The absorption flux rate profiles with DMSO continued increasing but bipeak-featured profiles were observed with acetone. SLS enhanced PA absorption with both DMSO and acetone. The presence of MNA in both vehicles blunted the absorption rate curves without significantly changing total absorption. SnCl2 blocked PA absorption and increased residue level on the skin surface and in the stratum corneum (SC). The venous flux profiles were mixture-dependent and highly reproducible within treatment groups. Higher level interactions were also noted. This study indicated multiple levels of interactive effects on PA absorption which must be incorporated into any effort to identify critical mechanisms which affect risk assessment of topically exposed mixtures. It was suggested that the chemicals selected in a topically applied mixture may have significant effects on the penetration/distribution pattern and percutaneous absorption profile of a toxicant/drug in the mixture. The MDCM approach may be useful in a screening or triage approach to identify mixture components which affect marker chemical absorption as well as identify potential mechanisms which deserve further attention. Risk assessment efforts could then be focused on those mixtures, containing these critical components, which would be expected to have the greatest penetration and absorption.

The use of mechanistically defined chemical mixtures (MDCM) to assess mixture component effects on the percutaneous absorption and cutaneous disposition of topically exposed chemicals. II. Development of a general dermatopharmacokinetic model for use in risk assessment.

We present a conceptual approach to a general comprehensive mathematical model to quantify percutaneous absorption of topically applied chemicals in complex mixtures on the basis of biophysical parameters estimated or measured using in vitro and ex vivo perfused skin preparations. This model addresses mechanistically defined chemical mixtures (MDCM) which consist of components selected because of their potential to modulate by various mechanisms the absorption of a marker toxic penetrant. This model accounts for observed toxicodynamic general and specific effects of chemicals, acting single or in concert, on the absorption of any or all components in a defined mixture. We have also included experimental data from an isolated perfused porcine skin flap study with topically applied parathion as the marker penetrant and acetone or DMSO as solvent, with methyl nicotinate as a potential rubefacient, sodium laurel sulfate as a surfactant, and stannous chloride as a reducing agent in order to provide an illustration of the application and performance of the model. This model supports the MDCM concept that defining and then simulating those components of a complex mixture that could have a significant impact on the absorption of a marker toxic compound would be a useful screening approach in the risk assessment of topical chemical mixtures. It may also be used to identify critical pathways where chemical mixture component interactions significantly modify the absorption of the penetrant of interest.

Comparative plasma and tissue pharmacokinetics and drug residue profiles of different chemotherapeutants in fowls and rabbits.

Blood and tissue pharmacokinetics and drug residue profiles of six chemotherapeutants were studied. Ceftriaxone (CEF), intravenously at 50 mg/kg, sulfamonomethoxine (SMM) and sulfaquinoxaline (SQ), orally at 200 mg/kg, and olaquindox (OLA), orally at 50 mg/kg, were administered to young broilers. Penicillin (PEN), intramuscularly at 200,000 U/kg, and albendazole (ALB), orally at 20 mg/kg, were given to rabbits. For each drug, 13-18 groups (n = 5-10 individuals/group) of the dosed animals were killed at different post-dosing times. Drug and/or metabolite concentrations in plasma, liver, kidney, heart, lung, and muscle tissues were analysed by HPLC procedures. Multi-exponential kinetic models were fitted to the observed tissue concentration-time data by applying a non-linear least-squares regression computer program. Tissue half-life, peak tissue concentration, and time of peak tissue concentration were determined. Half-life of CEF, SMM, SQ, OLA, PEN, ALB, and two metabolites of ALB (sulfoxide and sulfone) in various tissues ranged 0.6-1.4, 4.7-9.0, 4.5-18.9, 1.8-3.1, 0.9-3.0, 3.4-9.6, 5.0-16.1 and 7.4-12.2 h. The times required for CEF, SMM, SQ, OLA, PEN, and ALB residue concentrations to decline to 0.1 microgram/g in various tissues ranged from 5.0-11.6, 70.0-110.5, 114.0-179.8, 21.3-30.3, 4.1-24.8 and 47.8-84.4 h. Drug kinetic characteristics in tissues differed significantly from those in plasma, and also varied from tissue to tissue. It is necessary, therefore, to evaluate tissue kinetics when designing dosage regimens in tissue infection chemotherapy with these drugs. Knowledge of tissue kinetics is also important in predicting and controlling drug residues in edible tissues of food-producing animals.

Significant effects of application site and occlusion on the pharmacokinetics of cutaneous penetration and biotransformation of parathion in vivo in swine.

Increasing attention has been paid to the variables of application site and dosing method in quantitation of chemical percutaneous absorption. Following topical and intravenous application of [ring-U-14C]parathion (PA) in weanling pigs, we have determined, in a previous publication, the profiles of 14C and HPLC-separated paraoxon (PO), p-nitrophenol (PNP), and p-nitrophenyl beta-D-glucuronide (PNP-G) in plasma, urine, tissues, and dosing device. The purpose of the present paper was to analyze these data further, focusing on a quantitation of the effects of application site (back versus abdomen) and dosing method (occluded versus nonoccluded) on in vivo disposition of both the parent PA and its sequential metabolites PO, PNP, and PNP-G. Cutaneous and systemic disposition parameters were determined using a numerical simulation modeling approach and moments analysis. Mean systemic bioavailability values of 8.9-9.2% for abdomen and 14.7-19.7% for back were determined. Under different dosing conditions, 1-35% of the topical dose was metabolized dermally, and 9-19% systemically. Radioactivity in plasma and urine was predominantly contributed by PNP-G and PNP. Site differences in 14C percutaneous absorption were governed by the differences in transport of PA, PO, and PNP from epidermis into blood, by local tissue distribution, and by the cutaneous metabolism to PNP. Systemic bioavailability of PA was higher from the back than from the abdomen. Occlusion not only increased the amount of 14C absorption and shortened the mean residence time in most compartments but also altered the systemic versus cutaneous biotransformation pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Percutaneous absorption, biotransformation, and systemic disposition of parathion in vivo in swine. I. Comprehensive pharmacokinetic model.

Topical exposure to pesticides is a common route of entry for systemic effects. To quantify disposition of parathion (PA) and its major metabolites in a widely accepted animal model for human dermal risk assessment, a comprehensive pharmacokinetic model was formulated following [ring-UL-14C]PA topical (occluded and non-occluded dose of 300 micrograms, 40 micrograms/cm2 on the abdomen and back) and intravenous (300 micrograms) administration in vivo in female weanling pigs. The model was then confirmed with an intravenous p-nitrophenol (PNP) study. Total 14C as well as HPLC-separated PA, paraoxon (PO), PNP, and p-nitrophenyl-beta-D-glucuronide (PNP-G) profiles in plasma and urine, and 14C in blood, stratum corneum, dosed tissues, dosing device, and evaporative loss were determined. The model quantitates the evaporative loss, dosing device binding, percutaneous absorption, first-pass metabolism and its impact on the systemic metabolic profile of PA, as well as the distribution and excretion kinetics of both the parent compound and its metabolites. Model parameters and the simulated amount-time profiles were reported. Occlusion not only enhanced the partition of both PA and PNP into the stratum corneum from the dosed skin surface, but also slowed down the distribution of PA and PNP in the local dosed tissues. A significant finding was that occlusion also altered the first pass biotransformation of PA in the epidermis. PA, PO, and PNP were more easily absorbed into blood from the back than from the abdomen skin. The rate-limiting process in PA percutaneous absorption is the partitioning from skin surface into the stratum corneum.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic-pharmacodynamic modelling of meperidine in goats (II): Modelling.

Simultaneous pharmacokinetic-pharmacodynamic (PK-PD) models of meperidine in goats were established by utilizing the P3 wave of the cerebral evoked potentials as an analgesic measurement. An effect compartment linked to the central compartment was postulated in the models. The hypothetical drug amount in the effect compartment was related to the observed analgesia through the Hill equation. After intramuscular (i.m., n = 16) and intravenous (i.v., n = 13) dosing (5 mg/kg), the elimination rate constants of meperidine in the effect compartment (Ke0) were 0.3744 +/- 0.2546 and 0.1123 +/- 0.0428 min-1, drug concentrations in the effect compartment generating half maximal analgesia (EC(50)) were 0.70 +/- 0.33 and 0.41 +/- 0.26 microgram/ml, the maximal effects (Emax) were 89.63 +/- 15.63 and 85.92 +/- 9.64%, and the Hill coefficients (S) were 2.61 +/- 1.21 and 2.37 +/- 1.15, respectively. Ke0 and EC(50) with i.m. dosing were significantly greater than with i.v. injection. However, administration route had no influence on S, Emax and the total amount of effect (AUE). The predicted peak effect (Emax) of 64.44 +/- 14.64 and 66.02 +/- 11.51% were achieved at 14.7 +/- 7.4 and 8.5 +/- 2.2 min after i.m. and i.v. dosing, respectively. Peak analgesia appeared much later than peak plasma concentration, but simultaneously with peak CSF level both after i.m. and i.v. dosing. An obvious hysteresis was demonstrated between plasma concentration and analgesic effect. This study demonstrates that meperidine analgesia can be predicted using a PK-PD model, but not by PK data alone. Both i.m. and i.v. administration routes were evaluated kinetically and dynamically.

Pharmacokinetic-pharmacodynamic modelling of meperidine in goats (I): Pharmacokinetics.

Plasma and cerebrospinal fluid (CSF) pharmacokinetics of meperidine were investigated after intramuscular (i.m.) or intravenous (i.v.) administration at a dose of 5 mg/kg in adult goats. After i.m. dosing, the plasma profile was best described by a one-compartment open model. In healthy (n = 16) and post-operative (n = 16) goats, the parameters were, respectively: tmax 8.3 +/- 3.9 and 9.2 +/- 5.5 min, Vd 2.763 +/- 1.231 and 3.929 +/- 2.101 l/kg, Clb 0.125 +/- 0.036 and 0.087 +/- 0.025 l/kg/min, Ke 0.0563 +/- 0.0358 and 0.0271 +/- 0.0136 min-1. The plasma profile was best fitted by a two-compartment open model following i.v. injection. In this case, the parameters for healthy (n = 7) and post-operative (n = 13) goats were, respectively: Vd 5.212 +/- 1.992 and 5.085 +/- 2.288 l/kg, Clb 0.096 +/- 0.028 and 0.075 +/- 0.026 l/kg/min, beta 0.0211 +/- 0.0093 and 0.0160 +/- 0.0052 min-1. There were, however, a few individuals with a prolonged elimination phase. Bioavailability of i.m. meperidine was 66.5 +/- 15.8% in healthy (n = 6) goats, but much higher in postoperative (n = 10) ones at 94.6 +/- 30.0%. Meperidine diffused into and out of CSF according to a first-order rate process. The time-course of CSF drug concentration was simulated by a biexponential function. CSF kinetic parameters of i.m. meperidine for healthy (n = 7) and postoperative (n = 13) goats were: elimination rate constant (K(ef)) 0.0269 +/- 0.0131 and 0.0305 +/- 0.0177 min-1, peak CSF concentration time (Tmaxf) 15.9 +/- 5.0 and 17.0 +/- 6.9 min. For the i.v. dosed healthy (n = 6) and postoperative (n = 8) animals, K(ef) was 0.0408 +/- 0.0107, 0.0414 +/- 0.0123 min-1 and Tmaxf was 10.0 +/- 5.0 and 7.7 +/- 2.5 min, respectively. It was demonstrated that an obviously lower peak concentration can be reached significantly later in CSF than in plasma, and the kinetic behaviour of meperidine in plasma is different from that in the CSF, indicating meperidine analgesia might not be predicted by simple extrapolation from the kinetic data.

Effects of anatomical site and occlusion on the percutaneous absorption and residue pattern of 2,6-[ring-14C]parathion in vivo in pigs.

The effects of anatomical site and occlusion on the percutaneous absorption and residue pattern of total 14C were investigated following topical application of 2,6-[ring-14C]parathion onto four skin sites (300 micrograms/10 microCi; 40 micrograms/cm2) in weanling swine using occluded and nonoccluded dosing systems. The excretion profile was examined after iv administration. After dosing onto the abdomen, buttocks, back, and shoulder (N = 4/site), total urinary and fecal excretion (%dose) by 168 hr were, for the occluded system, 43.94 +/- 2.24, 48.47 +/- 7.85, 48.82 +/- 4.49, and 29.28 +/- 5.70%, and for the nonoccluded system, 7.47 +/- 2.16, 15.60 +/- 3.71, 25.00 +/- 8.75, and 17.41 +/- 1.76%, respectively. After iv dosing, 98.44 +/- 2.83% of the applied dose was excreted primarily via urine. The total recoveries for different sites ranged from 90.09 +/- 7.10 to 94.62 +/- 1.98% in the occluded system, 77.84 +/- 5.75 to 88.18 +/- 3.34% in the nonoccluded system, and 99.03 +/- 2.89% in the iv experiments. Time of maximal excretion rate was determined in the occluded system as abdomen (7.9 +/- 3.6 hr) < buttocks (9.4 +/- 2.6 hr) < shoulder (10.5 +/- 3.8 hr) < back (13.3 +/- 7.7 hr), but in the nonoccluded system as buttocks (11.9 +/- 3.6 hr) < shoulder (12.6 +/- 4.1 hr) < back (14.3 +/- 6.4 hr) < abdomen (16.9 +/- 7.1 hr). The percutaneous absorption from the shoulder was much lower than that from the other three sites under occluded conditions. However, if nonoccluded dosing was employed, absorption from the abdomen became the lowest, with shoulder and buttocks being similar, and the back the highest. Occlusion conceals the site difference and enhances both the extent and the rate of parathion percutaneous absorption in vivo. 14C residue pattern in tissues and dosing materials was site and dosing method dependent, all of which are factors which must be considered when assessing the risk of exposure to topically applied compounds.