Simultaneous Oral Administration Research Articles

Interaction between tylosin and bentonite clay from a pharmacokinetic perspective

The interaction between bentonite and tylosin was investigated in broiler chickens, based on pharmacokinetic characteristics obtained in vivo. Simultaneous oral administration of bentonite and tylosin significantly lowered plasma levels of tylosin and reduced the area under the plasma concentration-time curve (AUC(0-inf)), maximal plasma concentration (C(max)), time to maximal plasma concentration (T(max)) and relative oral bioavailability. The results prove unambiguously the binding of tylosin by bentonite. Simultaneous administration of tylosin (in the drinking water or feed) and bentonite (mixed in the feed as a mycotoxin binder) should therefore be avoided.

Rapid LC-ESI-MS-MS Method for the Simultaneous Determination of Sitagliptin and Pioglitazone in Rat Plasma and Its Application to Pharmacokinetic Study

A liquid chromatography tandem mass spectrometry (LC-MS/MS) based method was developed for the simultaneous monitoring plasma levels of Sitagliptin (STG) and Pioglitazone (PIO) for applicability to pharmacokinetic studies. The method was based on HPLC separation on the reversed phase Phenomenex Synergy C18 column (30 mm length, 4.6 mm internal diameter, and 4.0 μm particle size) at a temperature of 40?C using a binary gradient mobile phase consisting of methanol and 2 mM ammonium acetate buffer pH adjusted to 4.5 with acetic acid, at a flow rate of 1 mL?min?1. Tolbutamide was used as an internal standard. Detection of analytes was achieved with LC-MS/MS system in Multiple Reaction Monitoring (MRM) mode. The method was validated over concentration range of 10.98 - 2091.77 ng?mL?1 for SIT and 8.25 - 1571.63 ng?mL?1 for PIO and lower limit of quantification was 10.98 ng?mL?1 and 8.25 ng?mL?1 for STG and PIO respectively. Recoveries from spiked controls were within acceptance criteria for all the analytes and internal standard at all QC levels. Within batch and between batch accuracy for STG was found within 96.9% - 100.3% and for PIO was found within 100.0% - 104.3%. Within batch and between batch precision for STG was less than 3.1% CV (coefficient of variation) and for PIO was less than 5.3% CV at all concentrations levels. This method was successfully applied to monitor pharmacokinetics profile of both STG and PIO on simultaneous oral administration to rats. This method can be applicable for pharmacokinetic drug-drug interaction studies.

Role of dehydroepiandrosterone in management of glucocorticoid-induced secondary osteoporosis in female rats

The current study aimed to evaluate the potential role of dehydroepiandrosterone (DHEA) in the protection and intervention of glucocorticoid-induced secondary osteoporosis in female rats. For this purpose this study was conducted on five groups of female Sprague Dawley rats which were classified into: (1) negative control group received saline as vehicle, (2) osteoporotic group orally administered with prednisolone (5 mg/kg b.wt.) daily for six months, (3) positive control group orally administered with DHEA (250 mg/kg b.wt.) three times weekly for six months, (4) protective group orally administered with prednisolone daily with simultaneous oral administration of DHEA three times weekly for six months and (5) therapeutic group orally administered with prednisolone daily for six months then orally administered with DHEA three times weekly for other six months. The obtained data revealed that prednisolone administration resulted in significant decrease in serum osteocalcin (OC), 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2) D(3)) and osteoprotegerin (OPG) levels accompanied with significant increase in serum parathyroid hormone (PTH) and receptor activator nuclear factor kappa B ligand (RANKL) levels. Histopathological investigation of left femur bone showed that prednisolone administration produced compression of the reduced articular surface and atrophy of the epiphyseal bone. On the other hand, DHEA supplementation to osteoporotic rats increased serum OC, 1,25-(OH)(2) D(3) and OPG levels while decreased serum PTH and RANKL levels. Moreover, DHEA administration resulted in restoration of intact epiphyseal bony structure and articular surface. In conclusion, DHEA via its control on glucocorticoid activity and androgenic action provided potent effect on bone.

Development of a novel combination tablet containing trimebutine maleate and mosapride citrate for the treatment of functional dyspepsia

To develop a novel combination tablet which contained 100 mg trimebutine maleate and 5 mg mosapride citrate (TMCT) for the treatment of functional dyspepsia, the wet granulation method was used to prepare TMCTs with various amounts of diluents and stabilizers. The levels of impurities, the stability and the dissolution of the TMCTs were investigated. The oral bioavailability of drugs in the TMCTs was then evaluated and compared to the simultaneous oral administration of trimebutine maleate-loaded and mosapride citrate-loaded commercial products in the beagle dog. Among the diluents tested, d-mannitol was selected, since the microcrystalline cellulose and lactose did not inhibit the production of drug impurities due to their hygroscopic properties and chemical interactions, respectively. Furthermore, succinic acid was selected as the stabilizer because it gave the lowest level of total drug impurities of the organic acids tested. The combination tablet of trimebutine maleate and mosapride citrate prepared with D-mannitol and succinic acid gave a total drug content higher than 95% and total impurities lower than 0.5% at 25 °C/60% RH and 40 °C/75% RH during a 6-month period, indicating that the tablets were stable for at least 6 months. Furthermore, this combination tablet showed a similar dissolution to the trimebutine maleate-loaded and mosapride citrate-loaded commercial products and gave insignificantly different absorption compared to these commercial products in beagle dogs. Thus, the combination tablet of trimebutine maleate and mosapride citrate prepared with d-mannitol and succinic acid would be a stable and effective oral pharmaceutical product for the treatment of functional dyspepsia.

Influence of nicardipine and nifedipine on plasma carvedilol disposition after oral administration in rats

The effect of two kinds of 1,4-dihydropyridine calcium-channel blockers, nicardipine hydrochloride and nifedipine, on the disposition of carvedilol, was studied in rats. Blood samples were assayed for carvedilol levels using solid-phase extraction and high-performance liquid chromatography. The plasma carvedilol concentration was found to be significantly higher, and the area under the concentration-time curve up to 24 h (AUC0-->24) was 6.7 and 3.0 times higher after simultaneous oral administration of 20 mg kg(-1) carvedilol with 40 mg kg(-1) nicardipine hydrochloride, or with 40 mg kg(-1) nifedipine, respectively, than after administration of carvedilol alone. The pharmacokinetic interaction between carvedilol and dihydropyridine calcium-channel blockers is thought to be attributable to vasodilator-induced changes in hepatic first-pass metabolism, inhibition in the absorption barrier by P-glycoprotein and in the metabolism of carvedilol.

Monoketocholate can decrease transcellular permeation of methotrexate across Caco-2 cell monolayers and reduce its intestinal absorption in rat

Abstract Objectives Bile salts have been shown to decrease the absorption of methotrexate in the rat intestine by an unknown mechanism. We aimed to examine this effect. Methods We assessed apical-to-basolateral (AP-BL) permeation of methotrexate (5 μM) across Caco-2 cell monolayers pretreated with various concentrations (0, 0.25, 0.5, 1, 3 and 5 mm) of sodium cholate or its semisynthetic analogue, sodium 12-monoketocholate. We also determined the effect of orally administered 12-monoketocholate on the intestinal absorption of methotrexate in rats to evaluate a possible in-vitro–in-vivo correlation. Key findings It was found that sodium cholate and sodium 12-monoketocholate decreased the AP-BL permeation of methotrexate at low concentrations (maximal inhibition at 0.25 and 1 mm, respectively) and increased it at higher concentrations. Determination of [14C] mannitol permeation and electrical resistance of monolayers during experiments showed that membrane integrity was not compromised at low concentrations of bile salts but was disrupted at higher concentrations. Subsequently, we examined the effect of the simultaneous oral administration of sodium 12-monoketocholate (4, 20, 40 and 80 mg/kg) on the intestinal absorption of methotrexate in rats after an oral dose (5 mg/kg). The pharmacokinetic study showed that 12-monoketocholate at 4 and 20 mg/kg did not change the methotrexate area under the serum concentration–time curve whereas sodium 12-monoketocholate at 40 and 80 mg/kg significantly reduced it. Conclusions Sodium 12-monoketocholate appears to decrease the intestinal absorption of methotrexate in rats by inhibition of transcellular active transport.

Monoketocholate can decrease transcellular permeation of methotrexate across Caco-2 cell monolayers and reduce its intestinal absorption in rat

Bile salts have been shown to decrease the absorption of methotrexate in the rat intestine by an unknown mechanism. We aimed to examine this effect. We assessed apical-to-basolateral (AP-BL) permeation of methotrexate (5 muM) across Caco-2 cell monolayers pretreated with various concentrations (0, 0.25, 0.5, 1, 3 and 5 mM) of sodium cholate or its semisynthetic analogue, sodium 12-monoketocholate. We also determined the effect of orally administered 12-monoketocholate on the intestinal absorption of methotrexate in rats to evaluate a possible in-vitro-in-vivo correlation. It was found that sodium cholate and sodium 12-monoketocholate decreased the AP-BL permeation of methotrexate at low concentrations (maximal inhibition at 0.25 and 1 mM, respectively) and increased it at higher concentrations. Determination of [(14)C] mannitol permeation and electrical resistance of monolayers during experiments showed that membrane integrity was not compromised at low concentrations of bile salts but was disrupted at higher concentrations. Subsequently, we examined the effect of the simultaneous oral administration of sodium 12-monoketocholate (4, 20, 40 and 80 mg/kg) on the intestinal absorption of methotrexate in rats after an oral dose (5 mg/kg). The pharmacokinetic study showed that 12-monoketocholate at 4 and 20 mg/kg did not change the methotrexate area under the serum concentration-time curve whereas sodium 12-monoketocholate at 40 and 80 mg/kg significantly reduced it. Sodium 12-monoketocholate appears to decrease the intestinal absorption of methotrexate in rats by inhibition of transcellular active transport.

Anti-Diabetic Activity of a Leaf Extract Prepared fromSalacia reticulatain Mice

The effects of a water extract prepared from the leaves of Salacia reticulata on the absorption of sugars in normal and type 1 diabetic mice were investigated. The simultaneous oral administration of the extract at a dose of 1.0 mg/mouse with maltose or sucrose inhibited the postprandial elevation of the plasma glucose and insulin levels and intestinal alpha-glucosidase activities in mice. In addition, the supply of a 0.01% solution of the extract as drinking water prevented the elevation of the plasma glucose level and intestinal alpha-glucosidase activities in type 1 diabetic mice. This treatment also prevented the elevation of the plasma, pancreatic, and kidney lipid peroxide levels, lowering of the plasma insulin level, and elevation of the kidney aldose reductase activities in diabetic mice. These results suggest that the water extract of the leaves of S. reticulata could be a beneficial food material for the prevention of diabetes and obesity because of its multiple effects.

Pharmacokinetic Interaction Between Oltipraz and Silymarin in Rats

To evaluate the pharmacokinetic interaction between oltipraz and silymarin after intravenous and oral administration of both drugs to male Sprague-Dawley rats. Oltipraz (single doses of 10 and 30 mg/kg for intravenous and oral administration, respectively), silymarin (single doses of 50 and 100 mg/kg for intravenous and oral administration, respectively, and 14 days oral administration of 100 mg/kg), alone and together were administered to control rats. The pharmacokinetic parameters of oltipraz did not significantly altered by silymarin. However, after intravenous administration of the drugs together, the AUCs of unconjugated, conjugated, and total (unconjugated plus conjugated) silibinin were significantly different (32.7% decrease, and 32.1% and 27.2% increase, respectively), and total and (CL) and non-renal (CL NR ) clearance of unconjugated silibinin were significantly faster (49.4% and 61.1% increase, respectively) than those of silymarin alone (without oltipraz). After oral administration of silymarin with or without oltipraz, however, the pharmacokinetic parameters of unconjugated, conjugated, and total silibinin were comparable. After single intravenous administration of the drugs together, the AUC of unconjugated silibinin was significantly smaller, but that of both conjugated and total silibinin was significantly greater. This could have been due to an increase in the formation of conjugates (glucuronidation and sulfation) of silibinin as induced by oltipraz. After simultaneous oral administration of the drugs, however, the AUCs (or AUC 0-12 h) of unconjugated, conjugated, and total silibinin were comparable.

Effects of a dopamine receptor agonist and atropine sulfate on absorption of valproic acid in rats

The aim of this study is to determine whether pramipexole hydrochloride hydrate (PHH) and atropine sulfate affect valproic acid (VPA) pharmacokinetics and to evaluate how plasma VPA concentrations are altered by different PHH administration routes. The following studies were conducted on rats: 1) changes in plasma VPA concentration after simultaneous oral administration (PO) of PHH and VPA-Na; 2) effects of intraperitoneal administration (IP) of PHH on plasma VPA concentration after VPA-Na PO; 3) effects of PHH PO on plasma VPA concentration after intravenous administration (IV) of VPA-Na; and 4) changes in plasma VPA concentration after simultaneous PO of atropine sulfate and VPA-Na. Atropine sulfate PO significantly decreased the area under the concentration-time curve up to 3 h (AUC0-3, the total amount of drug plasma concentration) of VPA, suggesting that atropine sulfate decreases VPA-Na absorption probably due to reduced gastrointestinal motility by its anticholinergic action. Similarly, by PHH PO or IP, VPA AUC0-3 was significantly decreased. However, in cases of VPA-Na IV, all VPA parameters were unchanged by PHH PO. These results indicate that the PHH inhibitory effect may be caused in the absorption phase of VPA by pharmacological action of PHH, and thus PHH decreases VPA-Na bioavailability.

Synergistic effect of tincture of Crataegus and Mangifera indica L. extract on hyperlipidemic and antioxidant status in atherogenic rats

This study was designed to address the synergistic effect of tincture of Crataegus (TCR) and Mangifera indica L. (MNG) extracts on the lipid and antioxidant parameters in the development of aortic lesions in diet-induced atherosclerosis in rats. TCR, is an alcoholic extract made from the berries of Hawthorn, Crataegus oxyacantha with flavanoids as the main constituent. MNG, is an alcoholic extract made from the stem bark of Mangifera indica L. with polyphenols as the main constituent. Simultaneous oral administration of these two extracts (0.5 ml/100 g body weight) to rats fed with an atherogenic (4% cholesterol, 1% cholic acid, 0.5% thiouracil) diet prevented the elevation of lipids in the serum and heart and also caused a significant decrease in lipid accumulation in the liver and aorta reverting the hyperlipidaemic condition of these rats. These extracts significantly restored the activity of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione, thereby restoring the antioxidant status of the organism to almost normal levels. This effect could be attributed to the synergistic activity of flavonoids in TCR and polyphenols of MNG.

Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride

Distal renal tubular acidosis (RTA) can lead to rickets in children or osteomalacia in adults if undetected. This disorder is normally diagnosed by means of an oral ammonium chloride-loading test; however, the procedure often leads to vomiting and abandonment of the test. In this study, we assess an alternative, more palatable approach to test urinary acidification. This was achieved by the simultaneous oral administration of the diuretic furosemide and the mineralocorticoid fludrocortisone to increase distal tubular sodium delivery, principal cell sodium reabsorption, and alpha-intercalated cell proton secretion. We evaluated 11 control subjects and 10 patients with known distal RTA by giving oral ammonium chloride or furosemide/fludrocortisone in random order on separate days. One control and two patients were unable to complete the study owing to vomiting after NH4Cl; however, there were no adverse effects with the furosemide/fludrocortisone treatment. The urine pH decreased to less than 5.3 in the controls with both tests, whereas none of the patients was able to lower the urine pH below 5.3 with either test. We conclude that the simultaneous administration of furosemide and fludrocortisone provides an easy, effective, and well-tolerated alternative to the standard ammonium chloride urinary acidification test for the diagnosis of distal RTA.

Human biokinetics of strontium—part II: Final data evaluation of intestinal absorption and urinary excretion of strontium in human subjects after stable tracer administration

Fractional intestinal absorption (f1 value) and urinary excretion of strontium in healthy human volunteers has been measured by simultaneous oral and intravenous administration of the stable isotopes 86Sr and 84Sr using the double-isotope method. Final evaluation of the complete data set confirmed that ingestion of different foodstuff and nutritional factors could influence the fractional gut uptake of strontium. In some cases, significant deviations from the f1 value adopted by the International Commission on Radiological Protection (ICRP) were found. The arithmetic mean (+/- standard deviation) of the f1 values of all experiments performed was determined to be 0.46 (+/- 0.24). The probability distribution function of the f1 values is represented by a lognormal curve with a geometric mean of 0.38 and a geometric standard deviation of 2.06. Urinary excretion in all subjects varied depending on the administered foodstuff in a wide range and differs from the ICRP model, up to 2 days after tracer administration. No age or gender dependence of the absorbed strontium fraction and of the urinary excretion of strontium after an oral load was found.

Inhibition of Testosterone-Induced Hyperplasia of the Prostate of Sprague-Dawley Rats by Pumpkin Seed Oil

The oil from the pumpkin (Cucurbita pepo) seed is claimed to be useful in the management of benign prostatic hyperplasia. This investigation seeks to examine the effect of pumpkin seed oil on testosterone-induced hyperplasia of the prostate of rats. Hyperplasia was induced by subcutaneous administration of testosterone (0.3 mg/100 g of body weight) for 20 days. Simultaneous oral administration of either pumpkin seed oil (2.0 and 4.0 mg/100 g of body weight) or corn oil (vehicle) was also given for 20 days. The weights of the rats were recorded weekly, and the influence of testosterone and pumpkin seed oil on the weight gain of the rats was examined. On day 21, rats were sacrificed, and the prostate was removed, cleaned, and weighed. The prostate size ratio (prostate weight/rat body weight) was then calculated. Neither testosterone nor pumpkin seed oil had any significant influence on the weight gain of the rats. Testosterone significantly increased prostate size ratio (P < .05), and this induced increase was inhibited in rats fed with pumpkin seed oil at 2.0 mg/100 g of body weight. The protective effect of pumpkin seed oil was significant at the higher pumpkin seed oil dose (P < .02). We conclude pumpkin seed oil can inhibit testosterone-induced hyperplasia of the prostate and therefore may be beneficial in the management of benign prostatic hyperplasia.

Human biokinetics of strontium. Part I: Intestinal absorption rate and its impact on the dose coefficient of 90Sr after ingestion

Intestinal absorption of strontium (Sr) in thirteen healthy adult German volunteers has been investigated by simultaneous oral and intravenous administration of two stable tracer isotopes, i.e. (84)Sr and (86)Sr. The measured Sr tracer concentration in plasma was analyzed using the convolution integral technique to obtain the intestinal absorption rate. The results showed that the Sr labeled in different foodstuffs was absorbed into the body fluids in a large range of difference. The maximum Sr absorption rates were observed within 60-120 min after administration. The rate of absorption is used to evaluate the intestinal absorption fraction, i.e. the f (1) value for various foodstuffs. The equivalent and effective dose coefficients for ingestion of (90)Sr were calculated using these f (1) values, and they were compared with those recommended by the International Commission on Radiological Protection (ICRP). The geometric and arithmetic means of the f (1) values are 0.38 and 0.45 associated with a geometric standard deviation and a standard deviation of 1.88 and 0.22, respectively. The 90% confidence interval of the f (1) values obtained in the present study ranges from 0.13 to 0.98. Expressed as the ratio of the 95 and 50% percentiles of the estimated probability, the uncertainty for the f (1) value corresponds to a factor of 2.58. The effective dose coefficients of (90)Sr after ingestion are 6.1 x 10(-9) Sv Bq(-1) for an f(1) value of 0.05, 1.0 x 10(-8) Sv Bq(-1) for 0.1, 1.9 x 10(-8) Sv Bq(-1) for 0.2, 2.8 x 10(-8) Sv Bq(-1) for 0.3, 3.6 x 10(-8) Sv Bq(-1) for 0.4, 5.3 x 10(-8) Sv Bq(-1) for 0.6, 7.1 x 10(-8) Sv Bq(-1) for 0.8, and 7.9 x 10(-8) Sv Bq(-1) for 0.9, respectively. Taking the effective dose coefficient of 2.8 x 10(-8) Sv Bq(-1) for an f (1) value of 0.3, which is recommended by the ICRP, as a reference, the effective dose coefficient of (90)Sr after ingestion varies by a factor of 2.8 when the f (1) value changes by a factor of 3, i.e. it decreases from 0.3 to 0.1 or increases from 0.3 to 0.9, respectively.

Rates of intestinal absorption of molybdenum in humans

The intestinal absorption of molybdenum in healthy human volunteers has been measured by simultaneous oral and intravenous administration of the stable isotopes 95Mo and 96Mo, and the results were analysed using the convolution integral technique. The results showed that molybdenum ingested in liquid form was rapidly and totally absorbed into the circulation under ordinary intake regimes. The rates and extent of absorption were lower for composite meals, and also for increasing levels of administration. This information can be helpful in the application of the new ICRP model of the human alimentary tract.

Validation of the plasma half-life of 11α-deuterium cortisol as a sensitive index for the analysis of human 11β-HSD2 activity in vivo

This study is concerned with validating the measurement of the plasma half-life of 11α- 2H cortisol in an attempt to accurately assess the in vivo activity of 11β-HSD2 in man. Oral administration of 5 mg of cortisol- 13C 4, 2H 1 to a human subject after repeated ingestions of 130 mg/day of glycyrrhetinic acid for 5 days resulted in a decrease in the rate constant of the cortisol- 13C 4, 2H 1 to cortisone- 13C 4 conversion, a direct index reflecting 11β-HSD2 activity. The reduced 11β-HSD2 activity led to an increase in the elimination half-life of cortisol- 13C 4, 2H 1, indicating that the loss of 11α- 2H is a sensitive in vivo means of assessing 11β-HSD2 activity. A simultaneous oral administration of 3 mg each of [1,2,4,19- 13C 4,11α- 2H]cortisol (cortisol- 13C 4, 2H 1) and 11α- 2H cortisol to another human subject confirmed the bioequivalency of the two labeled cortisols. The information obtained from the kinetic analysis of the 11β-HSD2-catalyzed conversion of cortisol- 13C 4, 2H 1 to cortisone- 13C 4 indicated that the elimination half-life of 11α- 2H cortisol was a sensitive index of renal 11β-HSD2 activity. The use of 11α- 2H cortisol as a tracer appears to offer a significant advance in evaluating human 11β-HSD2 activity in vivo.

Intrinsic factor studies: II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B 12

The simultaneous oral administration of normal human gastric juice and small quantities of vitamin B12 results in hematopoiesis in patients with pernicious anemia in relapse, while oral vitamin B12 alone in similar amounts is usually ineffective. 1 Berk L. Castle W.B. Welch A.D. Heinle R.W. Anker R. Epstein M. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. X. activity of vitamin B12 as food (extrinsic) factor. N Engl J Med. 1948; 239: 911 Google Scholar , 2 Schilling R.F. Harris J.W. Castle W.B. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. XIII. Hematopoietic activity of (vitamin B12). Blood. 1951; 6: 228 Google Scholar , 3 Ungley C.C. Absorption of vitamin B12 in pernicious anemia. BMJ. 1950; 2: 905 Google Scholar , 4 Hall B.E. Morgan E.H. Campbell D.C. Oral administration of vitamin B12 in pernicious anemia. I. Presence of intrinsic factor in Berkefeld-filtered pooled human gastric juice: Preliminary report, Proc Staff Meet. Mayo Clin. 1949; 24: 99 Google Scholar , 8 Hall Byron E. Studies on the nature of the intrinsic factor of castle. BMJ. 1950; 2: 585 Google Scholar The hematopoietic activity of intravenously administered vitamin B12 was not enhanced by the simultaneous intravenous administration of sterile Berkefeld filtered gastric juice in amounts known to be active as intrinsic factor when given orally. 5 Wallerstein R.O. Harris J.W. Schilling R.F. Castle W.B. Observations on the etiologic relationship of achylia gastrica to pernicious anemia. XV. Hematopoietic effects of simultaneous intravenous and of simultaneous or serial oral administration of intrinsic factor in vitamin B12. J Lab Clin Med. 1953; 41: 363 Google Scholar Vitamin B12 by parenteral injection regularly corrects the hematologic abnormalities and arrests the neurologic disorder in pernicious anemia. Heinle and associates 6 Heinle R.W. Welch A.D. Scharf V. Meacham G.C. Prusoff W.H. Studies of excretion (and absorption) of Co60-labeled vitamin B12 in pernicious anemia. Trans Assoc Am Phys. 1952; 65: 214 Google Scholar have reported that the fecal exeretion of radioactivity in four pernicious anemia patients receiving 0.5 μg of radioactive vitamin B12 (B12Co60) by mouth was definitely greater than in normal subjects. They reported that the simultaneous oral administration of an intrinsic factor preparation and B12Co60 in three pernicious anemia patients was followed by a definite reduction of fecal radioactivity. The simplest interpretation of the above information is that the function of intrinsic factor is to promote the absorption of vitamin B12 from the intestinal tract.

Gefitinib Enhances the Antitumor Activity and Oral Bioavailability of Irinotecan in Mice

As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [(14)C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.

Peroxynitrite-mediated oxidative modification of low-density lipoprotein by aqueous extracts of cigarette smoke and the preventive effect of fluvastatin

Cigarette smoking is known to promote atherosclerosis, possibly through enhanced oxidative stress. The aim of the present study was to elucidate the possible involvement of peroxynitrite in oxidative modification of low-density lipoprotein (LDL) induced by aqueous extract of cigarette smoke (CSE) and the preventive effect of fluvastain, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with antioxidative activity, in vitro and in vivo. Modification of LDL was monitored by LDL subfraction analysis using anion-exchange HPLC, TBARS formation and 3-nitrotyrosine production. Incubation of LDL with CSE caused a marked increase in oxidative modification of LDL and nitration of tyrosine residues in the apolipoprotein B. These modifications were prevented by treatment with fluvastatin as well as Vitamin E in a concentration-related manner. Fluvastatin was equal to or more effective than Vitamin E for preventing protein nitration, but weaker for preventing oxidative modification. When CSE was injected daily into the ear vein of Watanabe heritable hyperlipidemic rabbits for 5 months, both oxidative modification and nitration of the plasma LDL noticeably occurred. These changes induced by CSE could be effectively prevented by the simultaneous oral administration of fluvastatin (10 and 30 mg/kg) or Vitamin E (150 mg/kg). Fluvastatin prevented the LDL nitration more effectively than Vitamin E. These results suggest that peroxynitrite in CSE is involved in oxidative modification of LDL and that fluvastatin can efficiently prevent LDL modification by scavenging peroxynitrite. Fluvastatin may be potentially beneficial to hypercholesterolemic patients with oxidative stress such as smoking.