Phenolsulfonphthalein Research Articles

Modification in the electronic parameters of M/p-Si hybrid device by PSP functional dye interface with different contact metals (M:Ag, Cu, Pd, Sn)

In this study, a functional organic dye of phenol-sulfonphthalein (PSP) was used as an interfacial layer via a spin coating method, its impact on the electronic parameters including Schottky barrier height (Фb), ideality factor (n) and series resistance (Rs) was investigated for different top metal contacts. An Al metal was employed for Ohmic contact, while Schottky contacts were formed using different metals as Ag, Cu, Pd, and Sn metals via thermal evaporation technique during the fabrication process of M/PSP/p-Si hybrid devices (M: Ag, Cu, Pd, Sn) and their references (M/p-Si). The electrical performance of all references and Ag/PSP/p-Si, Cu/PSP/p-Si, Pd/PSP/p-Si, and Sn/PSP/p-Si hybrid structures were evaluated by performing current-voltage (I-V) and capacitance-voltage (C-V) measurements at the room temperature. The obtained results confirm that barrier height of all devices with and without the PSP organic interlayer depends on metal work function. The PSP interface layer leads to increase in barrier height value of the M/PSP/p-Si devices as compared to that of reference (M/p-Si) ones. This increment value for hybrid structures with the presence of PSP layer related with the metal work function for Ag, Cu, Pd, and Sn top metal. The highest Фb value of 0.760 eV and the lowest one as 0.618 eV were obtained by TE theory for the Sn/PSP/p-Si, Ag/PSP/p-Si device, respectively. The obtained results confirmed that PSP interface material and the work function of top contact metals are strongly impact on the modifying of the electronic parameters of fabricated devices.

Voriconazole injection may induce delayed methotrexate excretion: a case report and experimental study

BackgroundWe report a case of delayed excretion of methotrexate (MTX) in a pediatric patient on high-dose MTX therapy in response to a change in the concomitant dosage of voriconazole from oral to intravenous. As the intravenous, but not the oral formulation of voriconazole includes sulfobutylether-β-cyclodextrin (SBECD), which has an anionic residue, we hypothesized that SBECD inhibits the renal excretion of anionic compounds.MethodsWe evaluated the inhibitory effects of SBECD on renal excretion of phenolsulfonphthalein (PSP), which is eliminated in urine via organic anion transport systems. PSP was administered intravenously to rats at 2.5 and 25 mg/kg with or without SBECD pretreatment (320 mg/kg).ResultsThe plasma concentration of PSP at the dosage of 2.5 mg/kg were comparable between control and SBECD groups. On the other hand, at 25 mg/kg the elimination of PSP was delayed. The clearance of PSP at the dosage of 25 mg/kg was 9.71 ± 1.65 and 4.13 ± 0.76 mL/min/kg in control and SBECD groups, respectively (p < 0.05). This suggested that SBECD partly inhibits the renal excretion of anionic drugs.ConclusionThe present case report discusses the delayed elimination of MTX in high dose therapy and possible mechanism involving SBECD as an excipient in concomitant drugs. It seems better to avoid choosing injection containing SBECD for patients undergoing HD-MTX treatment. Further studies are needed to confirm the inhibitory effects of SBECD on the renal excretion of MTX, especially in high-dose regimens.

Phenolsulfonphthalein as a surrogate substrate to assess altered function of the prostaglandin transporter SLCO2A1

The prostaglandin (PG) transporter SLCO2A1 regulates PGE2 signaling and interacts with many drugs, and SLCO2A1 defects is associated with PG metabolic disorders. This study aimed to characterize a non-metabolic phenolsulfonphthalein (PSP) transport mediated by SLCO2A1. PSP uptake by HEK293 cells expressing human SLCO2A1 (HEK/2A1 cells) was pH-independent and saturable with a Km value of 54.5 ± 9.5 μM PGE2 competitively inhibited PSP uptake with a Ki of 257.3 ± 22.8 nM. When PSP was intravenously (i.v.) injected, concentration-time curve showed a biphasic response. In Slco2a1-deficient (−/−) mice, AUCinf tented to decrease and the central distribution volume (V1) significantly increased, compared to wild-type (wt) counterparts. Intriguingly, Slco2a1-deficiency significantly reduced a ratio of tissue-to-plasma concentration in the lungs at 15 min after i.v. injection, suggesting that SLCO2A1 limits tissue distribution of PSP. In conclusion, these results prove that PSP is a potential surrogate for monitoring SLCO2A1 function, providing a new concept for diagnostics for the genetic diseases caused by defects in SLCO2A1 gene.

Ultrasonic degradation of aqueous phenolsulfonphthalein (PSP) in the presence of nano-Fe/H2O2

In this study, nano iron (nano-Fe) was successfully synthesized by sodium borohydride reduction of ferric chloride solution to enhance the ultrasonic degradation of phenolsulfonphthalein (PSP). The nano-Fe was characterized by scanning electron microscopy – energy dispersive spectroscopy (SEM-EDX), transmission electron microscopy (TEM), powder X-ray diffraction (XRD), attenuated total reflection – Fourier transform infrared spectroscopy (ATR-FTIR), and Brunauer, Emmett and Teller (BET) surface area determination. Experimental results demonstrated that a combined ultrasonic/nano-Fe/H2O2 system was more effective for PSP removal in combination than they were individually and there was a significant difference between the combined and single processes. The ultrasonic/nano-Fe/H2O2 degradation follows the Langmuir-Hinshelwood (L-H) kinetic model. The addition of nano-Fe and H2O2 to the ultrasonic reactor greatly accelerated the degradation of PSP (25 mg/L) from 12.5% up to 96.5%. These findings indicated that ultrasonic degradation in the presence of nano-Fe and H2O2 is a promising and efficient technique for the elimination of emerging micropollutants from aqueous solution.

D-Malate decreases renal content of α-ketoglutarate, a driving force of organic anion transporters OAT1 and OAT3, resulting in inhibited tubular secretion of phenolsulfonphthalein, in rats.

d-Malate inhibits a Krebs cycle enzyme and the tubular transport of α-ketoglutarate, an intermediate of the Krebs cycle and the driving force for rat organic anion transporter 1 (rOAT1) and rOAT3 in the kidney. This study examined the effects of d-malate on the rat organic anion transport system. The uptake of 6-carboxyfluorescein by HEK293 cells expressing rOAT1 or rOAT3 was not affected by d-malate and l-malate. Up to 60min after the intravenous injection of phenolsulfonphthalein (PSP), a typical substrate of the renal organic anion transporters, as a bolus to rats, 47.1% of the dose was recovered in the urine, and its renal clearance was estimated to be 8.60ml/min/kg. d-Malate but not l-malate interfered with its renal excretion, resulting in the delayed elimination of PSP from plasma. No effect of d-malate was recognized on creatinine clearance or the expression level of rOAT3 in the kidney cortex. d-Malate increased the plasma concentration of α-ketoglutarate. In addition, the compound greatly stimulated the renal excretion of α-ketoglutarate, implying that d-malate inhibited its reabsorption. The content of α-ketoglutarate was significantly decreased in the kidney cortex of rats administered d-malate. Collectively, this study shows that d-malate abrogates the tubular secretion of PSP, and the reduction of the renal content of α-ketoglutarate was proposed to be one of the mechanisms. A relationship between the reabsorption of α-ketoglutarate and the basolateral uptake of organic anion in the kidney is suggested.

Decolorization of Synthetic Textile Dye and Enzymes Production byImproved Strains of Pleurotus Species

In the present investigation the efficiency of three species of white rot fungui - Pleurotus and their improved dikaryons (heterokaryons) was assessed for decolorization of Phenol Red (Phenolsulfonphthalein or PSP) and production of lignin peroxidase (LiP), manganese peroxidase (MnP) and laccase enzymes. All the species of Pleurotus i.e. P. flabellatus, P. ostreatus and P. citrinopileatus decolorized PSP well. However, improved dikaryons Pfo 6X9 and Poc 9X6 decolorized the dye more effectively than three species of Pleurotus. The improved dikaryons also showed higher ligninolytic activity than the parental species. Poc 9X6 showed higher LiP (56.14 U), MnP (615.15 U) and Laccase (715.25 U) activity. In the present work different pH, age and concentration of inoculum and effect of surfactant i.e. sodium dodecyl sulphate (SDS) and Tween-80 were analyzed in order to determine the optimum ones to decolorize maximum concentration of dye. 5 ml of 10 days old culture on pH 5.5 and 0.1% Tween-80 supported maximum decolorization of PSP.

Effects of poloxamer 407-induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats.

Hepatic multidrug resistance-associated protein 2 (Mrp2) is responsible for the majority of the biliary elimination of endogenous and exogenous substances, therefore it is important to evaluate possible functional changes in Mrp2 activity under conditions of hyperlipidemia (HL). Thus, the present study assessed the protein expression and transporting activity of hepatic Mrp2 based on the in vivo biliary excretion of phenolsulfonphthalein (PSP) as a model anionic substrate for Mrp2 in poloxamer 407-induced hyperlipidemic rats (HL rats) and compared these values with those for control rats. The pharmacokinetics of mycophenolic acid (MPA) and mycophenolic acid-7-O-glucuronide (MPAG) were evaluated after the intravenous (5 mg/kg) and oral (10 mg/kg) administration of MPA to control and HL rats. In HL rats, the protein expression of hepatic Mrp2 and its biliary transporting activity exhibited significant reductions (by 24.3% and 24.6%, respectively) in the absence of a change in bile flow rate. Unexpectedly, HL and control rats showed comparable biliary excretion rates of MPAG due to the counter effects of the reduced expression and activity of Mrp2 and a 484% increase in the free fraction of MPAG in HL rats. The estimated biliary clearance value of free MPAG in HL rats was considerably slower (by 77.1%) than that in control rats. Although significant pharmacokinetic changes in total MPA and MPAG levels were not observed in HL rats, there was a marked increase in free MPA and MPAG levels. Clinically relevant pharmacokinetic changes in subjects with HL that are related to MRP2 could not be ruled out. Copyright © 2016 John Wiley & Sons, Ltd.

Effect of selective cyclooxygenase-2 inhibitor lumiracoxib on phenolsulfonphthalein disposition in rats.

Selective cyclooxygenase-2 inhibitor lumiracoxib was shown to have the strong inhibitory potencies on the renal organic anion transporter (OAT)1 and also on OAT3 from drug transport experiments. The purpose of this study was to examine the effect of lumiracoxib on disposition of phenolsulfonphthalein (PSP) - which is mainly excreted into urine via OATs - from in vivo experiments. After the intravenous injection of PSP and lumiracoxib into rats, pharmacokinetic analysis was performed. After the intravenous injection of PSP as a bolus, its plasma concentration decreased time-dependently. Until 60 min after the injection, 51.1% of the dose was recovered into urine. The simultaneous administration of lumiracoxib increased the plasma levels of PSP and reduced its urinary recovery to 23.6% of the dose. The pharmacokinetic analysis using a two-compartment model exhibited that lumiracoxib affected the parameters implying the elimination of PSP. The present study demonstrates that lumiracoxib interfered with urinary excretion of PSP in rats.

Caffeic acid inhibits organic anion transporters OAT1 and OAT3 in rat kidney

Some food components influence drug elimination. Previously, we found that caffeic acid, present in coffee, fruits, and vegetables, strongly inhibited human homologs of organic anion transporters (OATs) OAT1 and OAT3, which are responsible for renal tubular secretion of anionic drugs. In this study, we examined the effect of caffeic acid on drug transport by OAT1 and OAT3 in the rat kidney. The inhibitory effect of caffeic acid on rat OAT1 and OAT3 was assessed by drug uptake experiment using Xenopus laevis oocytes. Urinary excretion of phenolsulfonphthalein (PSP), a diagnostic agent secreted by renal OATs, was examined in rats, and the influence of caffeic acid was evaluated. Expression of rat OAT1 (rOAT1) and rOAT3 stimulated uptake of their typical substrates, p-aminohippurate and estrone sulfate, respectively, into oocytes, and caffeic acid inhibited them dose dependently. After intravenous injection of PSP in rats, 42.7% of the dose was excreted into urine up to 60 min, and the simultaneous administration of caffeic acid reduced it to 32.0%. These findings show that caffeic acid inhibits OAT1 and OAT3 in the rat kidney.

Effect of Intestinal Atrophy and Hepatic Impairment Induced by Parenteral Nutrition on Drug Absorption and Disposition in Rats

Long-term parenteral nutrition (PN) has a high risk of hepatic dysfunction and intestinal atrophy. The present study investigated the effect of PN-induced intestinal atrophy and hepatic impairment on drug pharmacokinetics by using 2 contrasting compounds: phenolsulfonphthalein (PSP) and cyclosporin A (CyA). PSP or CyA was administered to 7-day PN-fed Rats (PN rats) and sham operated rats (control rats) via intravenous (IV) or intraloop administration of the intestine. Pharmacokinetic parameters with 2-compartment analysis including area under the concentration vs time curve (AUC) and the permeability after in situ intraloop administration (P loop) were obtained from both concentration profiles after different administration routes. After IV administration of PSP to control and PN rats, there was no notable difference in any of the pharmacokinetic parameters. In contrast, after intraloop administration, AUC and P loop in PN rats were approximately 2.6- and 2.0-fold higher than that in control rats, respectively. On the other hand, after IV administration of CyA, the terminal half-life and total body clearance were prolonged and decreased in PN rats, respectively, resulting in 2.0-fold increase in AUC. After intraloop administration, the AUC of PN rats was increased to approximately 1.3-fold that of control rats, whereas no notable difference was observed in P loop. The intestinal permeability of PSP was enhanced by intestinal atrophy induced by PN, while the metabolism of CyA was diminished by hepatic impairment by PN. These results revealed the physicochemical property-based pharmacokinetic alterations during PN; for a more detailed understanding, however, further studies are needed.

Evaluation of changes in hepatic disposition of phenolsulfonphthalein, indocyanine green and fluorescein isothiocyanate-dextran at low temperatures using a rat liver perfusion system

The aim of this study was to determine the factor changing the hepatic disposition of a drug during hypothermia using a rat liver perfusion system. The livers of male Wistar rats were perfused at 37, 32 or 28°C in the single-pass mode. Venous outflow dilution patterns and biliary excretion rate patterns of phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, MW 4400) after the injection of a bolus into the perfused rat liver were analysed based on statistical moment theory. The first-pass extraction ratio (E(h) ) of PSP was significantly decreased at 32 and 28°C compared with 37°C. The biliary recovery of PSP and its conjugate was decreased and the biliary excretion was kept at a high concentration and was prolonged by low perfusion temperatures. ICG was almost extracted by a single-pass through the liver even at 32 and 28°C. The biliary recovery of ICG was significantly decreased at low temperature. Although the distribution volume of FD-4 as a vascular reference was not changed by perfusion temperature, the E(h) of FD-4 was decreased at 28°C although not markedly. The change in hepatic disposition of a drug at low perfusion temperatures differed according to disposition processes under hypothermia.

Developmental expression of renal organic anion transporters in rat kidney and its effect on renal secretion of phenolsulfonphthalein

Organic anion transporters (OAT1 and OAT3) and multidrug resistance-associated proteins (MRP2 and MRP4) play important roles in anionic drug secretion in renal proximal tubules. Changes in the expression of such transporters are considered to affect the tubular secretion of anionic drugs. The purpose of this study was to elucidate the developmental changes in the expression of OAT1, OAT3, MRP2, and MRP4 and their effects on the tubular secretion of drugs. The mRNA level of each transporter was measured by real-time PCR, and the protein expression was evaluated by Western blotting and immunohistochemical analysis. In addition, the tubular secretion of phenolsulfonphthalein (PSP) in infant (postnatal day 14) and adult rats was estimated based on in vivo clearance study. The protein expression of organic anion transporters were very low at postnatal day 0 and gradually increased with age. In postnatal day 14 rats, the expression of OAT1 and OAT3 seemed to be at almost mature levels, while MRP2 and MRP4 seemed to be at immature levels. Immunohistochemical analysis in the kidney of postnatal day 0 rats revealed OATs on the basolateral membrane and MRPs on the brush-border membrane. At postnatal day 0, the distribution of these transporters was restricted to the inner cortical region, while after postnatal day 14, it was identical to that in adult kidney. An in vivo clearance study revealed that the tubular secretion of PSP was significantly lower in postnatal day 14 rats than adult rats. These results indicate that age-dependent changes in organic anion transporter expression affect the tubular secretion of anionic drugs in pediatric patients.

Low-dose probenecid selectively inhibits urinary excretion of phenolsulfonphthalein in rats without affecting biliary excretion

Renal organic anion transport systems play an important role in the excretion of anionic drugs and toxic compounds. Probenecid has been used as a potent inhibitor of urinary and biliary excretion of anionic compounds mediated by transporters such as organic anion transporters and multidrug resistance-associated protein 2 (Mrp2). The purpose of this study was to optimize the dose of probenecid required for selective inhibition of urinary excretion of anionic compounds in rats, without inhibition of biliary excretion. Phenolsulfonphthalein (PSP), a model anionic compound that is excreted in urine and bile, was intravenously administered to rats after intraperitoneal injection of different doses of probenecid (0, 0.2, 2, 10, 100, 200 and 400 mg kg(-1) ). Treatment with 100, 200 or 400 mg kg(-1) probenecid decreased both renal clearance (CLr ) and biliary clearance (CLb ) of PSP, whereas 0.2 mg kg(-1) probenecid did not have any effect. Probenecid administered at doses of 2 and 10 mg kg(-1) decreased only CLr . The median effective doses of probenecid for inhibiting CLr and CLb were 0.925 and 23.9 mg kg(-1) , respectively. These data suggest that a low dose of probenecid selectively inhibits urinary excretion of PSP that may be mediated by organic anion transporters, without affecting biliary excretion that may be mediated by Mrp2.

Early and quantitative detection of cisplatin-induced nephrotoxicity by measurement of plasma PSP (phenolsulfonphthalein) half-life in rats.

Renal function following cisplatin injection in rats was assessed by measuring the half-life of plasma PSP. Changes in BUN, creatinine, plasma PSP half-life and urinary N-acetyl-beta-D-glucosaminidase (NAG) levels were determined in rats treated with 6.5 mg/kg i.v. of cisplatin. The highest values of BUN and creatinine were both observed on day 5. Half-life of plasma PSP was significantly prolonged on days 2 through 5 and reached a peak value on day 3. A significant increase in urinary NAG levels appeared on day 2 and the peak value was demonstrated on day 3. BUN, creatinine and plasma PSP half-life were also determined on days 3 and 5 following several doses of i.v. cisplatin. A dose-related increase in plasma PSP half-life was observed on day 3, while dose-related increases in BUN and creatinine levels were found on day 5. The evaluation of cisplatin-induced nephrotoxicity by the plasma PSP test was clearly superior for early detection compared with conventional renal function tests using BUN and creatinine.

Absence of drug interaction between Hwang-Ryun-Hae-Dok-Tang and Phenolsulfonphthalein

Hwang-Ryun-Hae-Dok-Tang (HT; a standardized herbal formula consisting of extracts from Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus) was reported to modulate a function of multidrug resistance associated protein 2 (Mrp2) in vitro. The aim of this study was to assess the in vivo pharmacokinetic interactions between HT and phenolsulfonphthalein (PSP), a typical model Mrp2 substrate eliminated via bile through Mrp2 in rats. Rats received intravenous PSP (0.8 mg/kg) followed by either a single oral dose of HT (0.42 g/kg) or multiple oral doses of HT (0.42 g/kg for 7 days). The effect of HT treatment was also investigated at a steady-state after intravenous PSP infusion. In contrast to previous in vitro results, in this study, we found that the HT-treated and control groups did not show any significant difference in the plasma PSP concentration and pharmacokinetic parameters, including area under the plasma concentration-time curve (AUC; control: 118 ± 19, single dose: 116 ± 40, and multiple dose: 137 ± 4, in mg/(min·mL)) and biliary clearance (control: 3.15 ± 0.69, single dose: 2.59 ± 1.11, and multiple dose: 2.53 ± 0.65, in mL/(min·kg)). However, cyclosporine A (5 mg/kg, an inhibitor of Mrp2) significantly decreased the AUC and biliary clearance of PSP. The steady-state plasma concentration and biliary clearance of PSP-were also similar between the groups. Taken together, our results suggest that HT may not be affected by Mrp2-mediated herb-drug interaction in vivo.

Changes in bowel mucosal permeability and wound healing after neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NAC) with 5-fluorouracil (5-FU) and cisplatin (CDDP) is a promising approach for locally advanced gastric cancer. We investigated the influence of NAC with 5-FU/CDDP on the permeability of intestinal mucosa and wound healing. Male Sprague Dawley rats were divided into four groups (n=6). Group 1 received saline (control group) and Groups 2-4 were administered preoperative 5-FU/CDDP (NAC groups). The NAC consisted of daily intraperitoneal administration of 5-FU from day 1 to 5 and from day 8 to 12 and intravenous administration of CDDP on days 2 and 9. The rats underwent gastrotomy (1.0 cm) with a laparotomy of 3 cm in length, under general anesthesia. Seven days after surgery, the rats were orally administered with phenolsulfonphthalein (PSP), and the 24-h urinary excretion of PSP was quantified. On postoperative day 8, the bursting pressure (BP) of the gastric suture line and the tensile strength of the abdominal wound were measured. The hydroxyproline (HP) content in the tissue of the abdominal suture line was then measured, and the number of fibroblast cells in the tissue of the gastric suture line was calculated by histopathological examination. The PSP urinary excretion rate was significantly higher in Group 2 in comparison with the other groups (P<0.05), while the BP of a selected gastrorrhaphy region was significantly lower in Group 2 (P<0.05). No significant differences were noted in the HP content. NAC with 5-FU/CDDP disturbs the healing of intestinal anastomoses when the interval between chemotherapy and surgery is insufficient. Neither HP content nor fibroblast counts were correlated with BP. Consequently, NAC appeared to affect the remodeling of collagen fiber. Thus, the integrity of the intestine may play a role in intestinal wound healing.

Functional analysis of phenolsulfonphthalein transport system in Long–Evans Cinnamon rats

It has been reported that the transport function for organic anions on the kidney is maintained in multidrug resistance-associated protein 2 (Mrp2)-deficient rats. Different from Mrp2-deficient rats, Long–Evans Cinnamon (LEC) rats have impaired urinary excretion of Mrp2-substrate, phenolsulfonphthalein (PSP). PSP is transported by the potential-sensitive urate transport system in rat brush-border membranes. We analyzed the function of PSP transport system in LEC rats. Unlike Long–Evans Agouti (LEA) rats, the initial uptake of PSP and urate into the renal brush-border membrane vesicles of LEC rats were not significantly enhanced in the presence of positive intravesicular potential, suggesting that the potential-sensitive urate transport system is impaired in LEC rats. LEC rats should be useful for elucidating the potential-sensitive urate transport system in rats at the molecular level.

Evaluation of Enhanced Peritoneum Permeability in Methylglyoxal-treated Rats as a Diagnostic Method for Peritoneal Damage

As peritoneal damage in long-term peritoneal dialysis therapy is a major problem correlated to patient prognosis, diagnosis of peritoneal damage is important. To develop a diagnostic method for peritoneal damage, we focused on hyperpermeability across the peritoneum in a pathogenic peritoneal damage condition. In this study, disposition characteristics of an intraperitoneally injected marker substance in peritoneal damaged rats were analyzed. Peritoneal damaged rats were prepared by intraperitoneal injection of a glucose degradation product, methylglyoxal (MGO), for five or ten consecutive days. Phenolsulfonphthalein (PSP), as a marker substance, was intraperitoneally or intravenously injected into MGO-treated rats. Subsequently, the PSP disposition characteristics were pharmacokinetically analyzed. In both cases of 5 and 10 days treatment of MGO, absorption of PSP after intraperitoneal injection was significantly enhanced. Plasma concentration and urinary excretion of PSP in MGO-treated rats were also higher than those in saline-treated rats in the early phase. On the contrary, there was no significant difference in terms of the pharmacokinetic parameters of intravenously injected PSP in saline- or MGO-treated rats. These results indicated that intraperitoneally injected MGO primarily acts on the peritoneal membrane; therefore, the peritoneal permeability of the marker substance was enhanced. We demonstrated that pharmacokinetic analysis of peritoneum permeability might be a potent diagnostic method for peritoneal damage in experimental animals and patients receiving peritoneal dialysis.

Change in Pharmacokinetics of Model Compounds with Different Elimination Processes in Rats during Hypothermia

We compared the pharmacokinetics of model compounds with different elimination processes between hypothermic and normothermic rats, to obtain basic information concerning drug therapy during hypothermia. Male Wistar rats were anesthetized with sodium pentobarbital and kept at temperatures of 37 degrees C (normothermic group) by heat lamp, and 32 degrees C or 28 degrees C (hypothermic group) by external cooling. We chose phenolsulfonphthalein (PSP), indocyanine green (ICG) and fluorescein isothiocyanate (FITC)-dextran (FD-4, Mw 4400) as model compounds to determine changes in clearance pathways during hypothermia therapy. The plasma concentrations of PSP as biliary, urinary and metabolic elimination type were increased significantly in the hypothermic group (32 degrees C, 28 degrees C) after i.v. administration at a dose of 1 mg, compared to the normothermic group (37 degrees C). Each PSP clearance (bile, urine and metabolites) in the hypothermic group was decreased, suggesting an influence of hypothermia on the active elimination process. The decreasing tendency was marked at a temperature of 28 degrees C. Moreover, the plasma concentrations of ICG as the biliary excretion type after i.v. administration to the hypothermic rats at a dose of 1 mg were higher with more than 50% decrease in the total body clearance compared to normothermic rats. On the other hand, there was almost no difference in the i.v. pharmacokinetics of FD-4 as the urinary excretion type between 37 degrees C and 32 degrees C. However, renal clearance of FD-4 was significantly decreased at a temperature of 28 degrees C. Accordingly, the change in pharmacokinetics of a drug in the hypothermic group could differ with the elimination processes.

Absorption characteristics of model compounds from the small intestinal serosal surface and a comparison with other organ surfaces

We examined the absorption of phenolsulfonphthalein (PSP) and fluorescein isothiocyanate dextrans (FD-4, MW 4400; FD-10, MW 9500; FD-40, MW 40 500) as model compounds through the small intestinal serosal surface. After application to the rat small intestinal serosal surface using a cylindrical diffusion cell, each compound was absorbed at different rates. The absorption ratios in 6 h after PSP, FD-4, FD-10 and FD-40 application were calculated to be 89.2, 34.6, 14.9 and 2.1% of dose, respectively. Elimination profiles of PSP, FD-4 and FD-10 from the small intestinal serosal surface obeyed first-order kinetics. Moreover, we calculated the apparent permeability coefficient P(app) for comparison to other organ surfaces. The kidney had the highest absorption efficiency, as shown by having more than 1.5 times significantly higher P(app) values of PSP, FD-4 and FD-10. Similar to the other organ surfaces, a correlation was observed between the P(app) of the small intestine and the molecular weight of these hydrophilic compounds. In addition, the small intestine is likely to contribute largely to hydrophilic compound absorption from the peritoneal cavity, judging from absorption clearance, CL(a), calculated using the peritoneal organ surface area.