Circulation,respiration, and blood homeostasis in cyanide-poisoned dogs after treatment with 4-dimethylaminophenol or cobalt compounds

The effects of intravenously injected 4-dimethylaminophenol-HCl (DMAP), Co₂EDTA, and Co(histidine)₂ on the survival rate and several physiological parameters were studied on dogs after acute intravenous poisoning with the double lethal dose of potassium cyanide.All dogs survived when the antidotes were administered 1 min after poisoning. When the therapy began 4 min after poisoning more dogs were rescued in the DMAP group than in the cobalt groups. DMAP, Co₂EDTA, and Co(histidine)₂ restored circulation and respiration of the surviving animals in a similar manner.The increase in the plasma concentrations of glucose and lactate was much higher in the Co₂EDTA group than in the DMAP group. The injection of Co₂EDTA produced a sharp rise in the lactate-to-pyruvate ratio. The lactate-to-pyruvate ratio stayed unchanged for some 15 min after injection of DMAP before also rising. The total dose of KCN (4 mg/kg) was bound to the ferrihemoglobin formed by DMAP. The arterial pO₂ increase, caused by liberation of oxygen from oxyhemoglobin during the formation of ferrihemoglobin, was less when the cyanide could act on the tissues for a longer period of time before the therapy with DMAP began.DMAP is more appropriate for the therapy of cyanide poisoning than Co₂EDTA, since the latter adds its inhibitory effects on the metablism to those of cyanide.     

Pharmacokinetics of cyanide in poisoning of dogs,and the effect of 4-dimethylaminophenol or thiosulfate

Cyanide in blood, plasma, and urine of dogs after administration of K¹⁴CN was determined with the isotope dilution technique. The addition of large amounts of inactive KCN as soon as possible to a sample to be analyzed inhibited the decrease of the original cyanide concentration.After administration of several lethal doses of cyanide into the stomach or by slow intravenous infusion a concentration of about 40 M cyanide in plasma was found at the moment of respiratory arrest. Since 60% of the cyanide in plasma was bound to proteins the concentration of free cyanide which stopped respiration was about 16 M.Quick formation of ferrihemoglobin by i.v. injection of 4-dimethylaminophenol after plasma cyanide had risen to or above 40 M decreased the cyanide concentration in plasma and restored respiration, while cyanide was accumulated in red cells by formation of ferrihemoglobin cyanide.Equilibrium constants calculated for the reaction between ferrihemoglobin and cyanide in vivo indicated that the reaction approached equilibrium in a few minutes.Up to 60% of the radioactive cyanide absorbed was found as non-cyanide radioactivity in the urine.Abbreviations Used DMAP 4-Dimethylaminophenol hydrochloride - HbFe²⁺ Ferrohemoglobin - HbFe³⁺ Ferrihemoglobin - HbFe³⁺CN^– Ferrihemoglobin cyanide - C_a Molarity of all radioactive compounds calculated on the assumption that one mole cyanide yields one mole metabolite - NCR Molarity of non-cyanide radioactive compounds calculated on the assumption that one mole cyanide yields one mole of metabolite (C_a-[CN^–])     

Effects of 4-dimethylaminophenol and Co2EDTA on circulation,respiration, and blood homeostasis in dogs

The effects of intravenously injected 4-dimethylaminophenol and Co₂EDTA on peripheral circulation, respiration, acid-base balance, and several other physiological and biochemical parameters were studied on dogs. DMAP increased the respiratory minute volume and mean arterial pressure, diminished the lactate-to-pyruvate ratio, and induced an increase in arterial oxygen pressure caused by liberation of oxygen from oxyhemoglobin during the formation of ferrihemoglobin.A study in vitro of the fate of the oxygen during the reaction between DMAP and oxyhemoglobin showed that only 30–40% of the oxygen released by the formation of ferrihemoglobin appeared in the gas phase.Co₂EDTA caused circulatory depression, hyperventilation, and metabolic acidosis resulting in a decrease in base-excess and pH. The concentrations of lactate, pyruvate, potassium, and urea nitrogen and the hemoglobin content were increased by Co₂EDTA. The side effects of Co₂EDTA in therapeutic doses were more serious than those of DMAP. Thus the latter is superior in the therapy of cyanide poisoning, all the more since it detoxifies more cyanide.     

A model for the induction of moderate levels of methaemoglobinaemia in man using 4-dimethylaminophenol

The induction of moderate levels of methaemoglobin by 4-dimethylaminophenol (DMAP) was studied in human and dog blood in vitro and in dogs in vivo. Although the rate of formation of methaemoglobin following intravenous injection into dogs was similar to that following addition of DMAP to dog blood in vitro, in the latter case levels fell more slowly. Addition of DMAP at the same concentrations in vitro resulted in more rapid oxidation of haemoglobin and higher peak levels of methaemoglobin in dog blood than in human blood. It was concluded that the rate of formation of methaemoglobin as well as the activity of methaemoglobin reductase must be considered when extrapolating data from the dog to man.     

Comparison of hydroxylamine, 4-dimethylaminophenol and nitrite protection against cyanide poisoning in mice

Intraperitoneal doses of 4-dimethylaminophenol hydrochloride (DMAP), hydroxylamine hydrochloride (H₂NOH) and sodium nitrite (NaNO₂) were found where each converted a maximum of about 37% of the total circulating hemoglobin in mice to methemoglobin. Those doses in mmol/kg were: 0.29 for DMAP, 1.1 for H₂NOH, and 1.1 for NaNO₂. For DMAP and H₂NOH the peak was sharp and at about 7 min after injection whereas for NaNO₂ the peak was much broader and at about 40 min. The i.p. LD₅₀'s in mmol/kg were: 0.48 for DMAP, 1.8 for H₂NOH and 2.3 for NaNO₂. When mice pretreated with each of the methemoglobin-generating agents were challenged with sodium cyanide, the ratios of the LD₅₀'s in protected mice to those in control mice (protection index, PI) were 1.5 for H₂NOH, 2.0 for DMAP and 3.1 for NaNO₂. When sodium thiosulfate was also given in combination with each of the three methemoglobin-generating agents, the protective effect was at least additive. The PI against sodium sulfide was also significantly greater in mice pretreated with NaNO₂ than in mice given H₂NOH. Methemoglobins generated from human and mouse hemoglobins by either NaNO₂ or by H₂NOH had identical binding affinities (dissociation constants) for cyanide. When human red cells containing methemoglobin generated by exposure to either NaNO₂ or H₂NOH were injected into the peritoneal cavity of mice and then followed by cyanide challenges, there was no difference in the PI for the two kinds of methemoglobin. Not only was the PI the same in each case with human cells, but it was also identical with that in mice given NaNO₂ systemically to generate the same total amount of methemoglobin. The difference in PI between NaNO₂ and H₂NOH (or DMAP) in mice appears to be related to the high rate of methemoglobin reductase activity in mouse RBC. It appears likely that cyanmethemoglobin is a substrate for mouse methemoglobin reductase activity, and that NaNO₂ is an inhibitor of mouse methemoglobin reductase. No differences in cyanide antagonism between NaNO₂ and H₂NOH would be anticipated in humans because of the slow rates of methemoglobin reduction in human red cells.     

Cerebral blood flow,circulation, and blood homeostasis of dogs during slow cyanide poisoning and after treatment with 4-dimethylaminophenol

The effects of 4-dimethylaminophenol · HCl (DMAP) and 100% oxygen on cerebral blood flow (CBF) and peripheral circulation, arterial and venous blood gases, and other parameters have been investigated in dogs in the course of slow cyanide infusion.The i.v. infusion of KCN increased the respiratory minute volume, accompanied by a rise in arterial pO₂ and pH and a decrease in arterial pCO₂ while the venous lactate concentration increased by about 500% and the hemoglobin content and hematocrit by about 30%. Heart rate and carotid artery blood flow decreased. Local CBF in the cingulum as measured with thermocouples rose steadily, and the brain and oesophagus temperature were lowered. The breathing of 100% oxygen raised the local CBF, the temperature, and the arterial pCO₂.During the infusion of KCN into the femoral artery of artificially ventilated dogs the femoral venous pO₂ increased continuously by some 40 mm Hg, attended with a decrease in pCO₂ of 15 mm Hg. The femoral blood flow, however, rose sharply within 3 min. 100% oxygen induced a rise in pCO₂ and a diminution of pH in the femoral vein and in the sinus sagittalis, and the femoral flow rose rapidly.After DMAP i.v. the values of most of the parameters returned to normal or finally stabilized below or above the initial level. The rise in the hemoglobin content, hematocrit, and lactate concentration was stopped, but the arterial and venous pH remained or were lowered. DMAP elicited a rapid, strong decrease in the pO₂ of the femoral vein and the sinus sagittalis with a concomitant marked increase in pCO₂.     

对二甲氨基酚治疗急性失血合并氰中毒对血液动力学及血液内环境的影响

本实验用犬制备了轻(10％)、中(15％)、重度(20％)急性失血合并ⅳ NaCN 2.5 mg/kg中毒的动物模型,观察了ⅳ DMAP 2.5mg/kg治疗时血液动力学及血液内环境的变化。结果发现,DMAP治疗轻度急性失血合并氰中毒能使心血管功能迅速恢复正常并维持稳定,随失血程度加重DMAP对心血管功能兴奋作用减弱;血气分析及HbFe~(3+)测定结果表明,DMAP治疗急性失血合并氰中毒可造成机体严重缺氧及代谢性酸中毒,并随失血程度的加重而加剧。     

Effects of 4-dimethylaminophenol,Co2EDTA,or NaNO2 on cerebral blood flow and sinus blood homeostasis of dogs in connection with acute cyanide poisoning

The effects of the cyanide antidotes DMAP, Co₂EDTA, and NaNO₂ on cerebral blood flow (CBF) and cerebral blood gases were investigated in connection with acute poisoning of dogs by cyanide. The substances were injected intravenously. Local CBF as measured with thermocouples in the cingulum increased by 100–200% after a non-lethal dose of KCN (1 mg/kg) and by 50% after injection of NaNO₂ (15 mg/kg), that oxidized some 20% of the total hemoglobin to ferrihemoglobin. Co₂EDTA (10 mg/kg) induced a decrease in local CBF of 30% and in brain temperature of 0.5°C. The temperature diminished also after poisoning by KCN, but it rose by 0.15°C after the administration of NaNO₂. Local CBF and sinus sagittalis blood flow increased by 60–160% for about 15 min, and the brain temperature decreased by 0.4–0.5°C when DMAP (3.25 mg/kg) or Co₂EDTA (15 mg/kg) was injected 1 min after poisoning by cyanide (4 mg/kg), a dose that always caused respiratory arrest. Immediately after injection of DMAP the brain temperature rose transiently by 0.1–0.2°C. Co₂EDTA did not exert such an effect. In the sinus sagittalis blood of artificially ventilated animals pCO₂ decreased rapidly by 10–20 mmHg after poisoning and approached the initial level after treatment with DMAP or Co₂EDTA. The highest value of pO₂ was about 80 mmHg and 50 mmHg after injection of DMAP and Co₂EDTA, respectively; thereafter pO₂ declined to 20 mmHg or 40 mmHg at 20 min. The lactate concentration increased by 60–70% without tendency to return to normal.     

Formation of cyanide after i. v. administration of the oxime HI 6 to dogs

HI6(pyridinium, 1-[[[4-(aminocarbonyl)pyridinio] methoxy]methyl]-2-[(hydroxyimino)methyl]-dichloride belongs to a series of bisquaternary pyridinium oximes that are effective against poisoning with extremely toxic organophosphates. Since HI6 has been shown to be unstable at pH 7.4 and to release significant amounts of cyanide, a study was undertaken to determine the degree of cyanide formation from HI 6 in vivo. When HI 6 (100 mol/kg) was administered i. v. to dogs, the animals showed no signs of cyanide toxicity but exhibited some cholinomimetic symptoms, including retching, hypersalivation and enhanced intestinal motility. Cyanide content in whole blood was monitored after production of methemoglobinemia (30%) by 4-dimethylaminophenol in order to sequester cyanide within red cells. Maximal cyanide contents of 20 mol/l were found in blood after 90 min. Calculation of the area under the concentration versus time curve for blood cyanide indicates that about 4% of HI 6 produced cyanide. Determination of the pharmacokinetic parameters of HI 6 (V_D=0.31 l/kg; k_el=0.76 h^–1) and of cyanide (V_D=0.086 l/kg; k_el=0.52 h^–1) together with the apparent first order rate constant of cyanide formation from HI 6 in vitro (0.174 h^–1, pH 7.4, 37°) allowed the simulation of a cyanide concentration curve that fitted with the experimental data points, indicating that cyanide formation in vivo was not bio-catalyzed. It is concluded that cyanide formation from HI 6 may not be regarded as a potential hazard, since cyanide elimination exceeded markedly its formation. Whether this conclusion also holds true for man has to be established.     

Efficacy of oral administration of sodium thiosulfate in a large,swine model of oral cyanide toxicity

IntroductionCyanide is a deadly poison, particularly with oral exposure where larger doses can occur before symptoms develop. Prior studies and multiple governmentagencies highlight oral cyanide as an agent with the potential for use in a terrorist attack. Currently, there are no FDA approved antidotes specific to oralcyanide. An oral countermeasure that can neutralize and prevent absorption of cyanide from the GI tract after oral exposure is needed. Our objective was toevaluate the efficacy of oral sodium thiosulfate on survival and clinical outcomes in a large, swine model of severe cyanide toxicity.MethodsSwine (45-55kg) were instrumented, sedated, and stabilized. Potassium cyanide (8 mg/kg KCN) in saline was delivered as a one-time bolus via an orogastric tube. Three minutes after cyanide, animals randomized to the treatment group received sodium thiosulfate (510 mg/kg, 3.25 M solution) via orogastric tube. Our primary outcome was survival at 60 minutes after exposure. We compared survival between groups by log-rank, Mantel-Cox analysis and trended labs and vital signs.ResultsAt baseline and time of treatment all animals had similar weights, vital signs, and laboratory values. Survival at 60 min was 100% in treated animals compared to 0% in the control group (p=0.0027). Animals in the control group became apneic and subsequently died by 35.0 min (20.2,48.5) after cyanide exposure. Mean arterial pressure was significantly higher in the treatment group compared to controls (p=0.008). Blood lactate (p=0.02) and oxygen saturation (p=0.02) were also significantly different between treatment and control groups at study end.ConclusionOral administration of sodium thiosulfate improved survival, blood pressure, respirations, and blood lactate concentrations in a large animal model of acute oral cyanide toxicity.     

Pharmacokinetics and Kinetic-Dynamic Modelling of Aminophenones as Methaemoglobin Formers

Methaemoglobin, the oxidized form of haemoglobin, can be formed by a variety of agents, most of which act to oxidize haemoglobin directly or indirectly. Cyanide has a higher affinity for methaemoglobin than for mitochondrial cytochromes, making methaemoglobin formation a basis for the treatment of cyanide poisoning. We used the beagle dog model to investigate the relationship between drug concentration and methaemoglobin levels for two candidate anti-cyanide compounds. The compounds studied were the aminophenones p-aminopropiophenone (PAPP) and p-aminoheptylphenone (PAHP). Both PAPP and PAHP were given as intravenous boluses and as two different oral formulations. The kinetics of both compounds appeared to follow a three-compartment open model for intravenous bolus administration and a two-compartment open model for oral administration. The first distribution phase seen with the intravenous administration was obscured by the absorption phase during oral administration. Bioavailability for all formulations varied between 20 and 47%. For both compounds there was a delay between the appearance of drug in the plasma and the appearance of methaemoglobin (counter-clockwise hysteresis) which is suggestive of an active metabolite causing methaemoglobin formation. The pharmacodynamics were fit with an effect-compartment kinetic-dynamic model linked to a sigmoid E_max pharmacodynamic model. Maximum amounts of methaemoglobin occurred between 2 and 4 h for PAHP and between 1 and 3 h for PAPP. When administered intravenously estimates of EC50 were lower than the estimates of EC50 from oral administration for both compounds. This might be because of oral first-pass inactivation or a ‘first-pass’ activation through the lungs contributing to the formation of an active metabolite. The phenones as a class appear to have the drug cleared and methaemoglobin return to near baseline within 12 h. Both compounds seem to produce sufficient methaemoglobin to treat acute cyanide poisoning and to serve as prophylactic agents against acute cyanide poisoning in a military setting.     

Simultaneous determination of hydrogen cyanide and volatile aliphatic nitriles by headspace gas chromatography,and its application to an in vivo study of the metabolism of acrylonitrile in the rat

A method for the simultaneous determination of hydrogen cyanide (HCN) and aliphatic nitriles using manual headspace (HS) gas chromatography (GC) with a capillary porous polymer column GS-Q and a nitrogen–phosphorus detector is described. With a HS incubation at 50°C for 30 min and a GC temperature at 180°C, HCN and volatile nitriles [acetonitrile, acrylonitrile (VCN), propionitrile, isobutyronitrile] were well separated and could be detected within 7 min with a detection limit of 0.7–2.4 ng/ml in blood samples. The HS-GC method was used in an in vivo study of VCN metabolism. VCN was administered orally (at nearly one-half its LD₅₀) to rats, and heart blood and urine were sampled. Blood concentrations of HCN and VCN were measured by HS-GC, and plasma and urinary thiocyanate concentrations were measured by the König colorimetric method. Blood levels of HCN and VCN peaked 1.5 h after VCN administration, at which time the cyanide level (about 0.7 g/ml) is close to the fatal level. HCN levels were observed to be at almost background levels at 10 h, although 50 ng/ml VCN was still detectable. The plasma thiocyanate level increased, reaching a peak (about 30 g/ml) at 5 h. The cumulative urinary thiocyanate amount gradually increased, and at 10 h more than 1 mg thiocyanate was excreted into the urine. It is therefore possible to clarify the cause of cyanide poisoning using HS-GC analysis, when someone has taken volatile nitriles.     

Formation of cyanide from o-chlorobenzylidene malononitrile and its toxicological significance

Mice received o-chlorobenzylidene malononitrile (CS) by i.p. injection (0.5 LD₅₀) or by aerosol exposure (20,000 mg min^–1 m^–3). Increased excretion of thiocyanate in the urine was observed, indicating a transformation of CS to cyanide in vivo. Determinations of cyanide in whole blood after i.p. administration of CS verified a rapid transformation of the agent to cyanide. A correlation between the time course of cyanide levels and symptoms was observed. Toxicity of injected CS was significantly reduced by pretreatment with thiosulfate, slightly reduced by nitrite and not affected by Co₂EDTA.Thiocyanate excretion, blood cyanide levels and protective effect of antidotes were also evaluated after administration of 0.5 LD₅₀ of malononitrile and potassium cyanide. The importance of cyanide formation for the toxicity of CS is discussed.     

Bioavailability of iron and cyanide from oral potassium ferric hexacyanoferrate(II) in humans

After oral administration of 500 mg KFe[Fe(CN)₆] labelled with⁵⁹Fe either in the ferric or ferrous position and with¹⁴C in the cyanide group only 0.22% of the Fe^II and <0.04% of the Fe^III were absorbed in three male volunteers. Only 2 mg non-complex bound relabelled cyanide (0.03 mg CN-/kg body wt) were absorbed from 500 mg [¹⁴C]KFeHCF, which is about a factor of 20–100 below the lethal dose in humans (0.5–3.5 mg CN-/kg body wt). Therefore, iron(III) hexacyanoferrates(II) can be considered as safe antidotes, i.e. for inhibiting the intestinal absorption of radiocaesium or for accelerating the excretion of already absorbed^134/137Cs in the case of a severe nuclear accident.     

Toxicokinetics of methyl paraoxon in the dog

The toxicokinetics of methyl paraoxon, the active metabolite of the organophosphorus insecticide methyl parathion, were studied in non-anaesthetized dogs after intravenous (2.5 mg/kg) and oral (15 mg/kg) administration of methyl paraoxon. After intravenous administration, distribution and elimination occured very rapidly and using the data from 5 min post-injection, the plasma concentration versus time curves could be fitted to a one-compartment open model. The mean half-life of elimination was 9.7 min, the average volume of distribution 1.76 l/kg and the average plasma clearance 126 ml/kg/min. After oral administration, peak plasma concentrations were obtained within 3–16 min, and the bioavailability varied from 5 to 71%. The hepatic extraction of methyl paraoxon measured in anaesthetized dogs, was high (70–92%). Comparison of the urinary excretion after intravenous and oral administration in two dogs indicated a gastrointestinal absorption of more than 60%. The kinetics of methyl paraoxon were linear in the dose range tested.     

Short-Chain Alkyl Esters of L-Dopa as Prodrugs for Rectal Absorption

The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable (>360 min) to hydrolysis in physiological buffer. In vitro enzymatic hydrolysis of the esters in plasma was species dependent, with the hydrolytic rate being faster in rat plasma (t _1/2 < 5 min) than dog plasma (t _1/2 = 68–181 min) or human plasma (t _1/2= 96–238 min). In vivo hydrolysis in dogs, as indicated by the L-dopa plasma profile following intravenous administration of the esters, was very rapid (high extravascular esterase activity). Significant L-dopa bioavailability was observed in rats following rectal administration of the methyl (46%), ethyl (14%), isopropyl (48%), butyl (100%), and 4-hydroxybutyl (13%) esters of L-dopa (rectal L-dopa absorption, <5%). In dogs, significant L-dopa bioavailability was also observed for the methyl (28%), isopropyl (30%), butyl (32%), and 4-hydroxybutyl (34%) esters of L-dopa in the presence of carbidopa. The data indicate that these highly water-soluble (>600 mg/ml) esters of L-dopa are potential candidates for controlled-release rectal delivery systems designed to provide more constant plasma L-dopa levels.     

Effects and biotransformation of 4-dimethylaminophenol in man and dog

The cyanide antidote 4-dimethylaminophenol . HCl (DMAP) was administered orally, i.v., or i.m. to man and dog. Ferrihemoglobin formation and changes of several parameters in human blood were investigated to obtain information on damage to liver, kidney, muscle, and red blood cells; in addition, the metabolism of DMAP was studied. In dogs, the initial rate of ferrihemoglobin production (DMAP, 3.25 mg/kg i.v. or i.m., 15 mg/kg orally) amounted to 28%, 3.5%, and 2% of the total hemoglobin per min; the corresponding values for man were 9%, 2%, and 2% per min. The dogs behaved normally while CPK increased after i.m. injection. In man, only i.m. injection of DMAP (3.25 mg/kg) was followed by increases in LDH, GOT, and CPK of 110, 260, and 490%, resp.; while total bilirubin, conjugated bilirubin, and iron concentration rose by 270, 120, and 50%, respectively. Bilirubin and iron concentration increased also after DMAP i.v. (3.25 mg/kg) or when it was taken orally (600 or 900 mg). The lactate concentration was not influenced while the pyruvate concentration increased by 50%. DMAP produced hemolysis in vitro. Generally, the values determined in vivo approached the starting level within 1 week. Intramuscular injection of DMAP induced reversible subjective and objective symptoms, e.g., local pain, swollen buttock, fever reaction. The urine showed no pathological changes. About 54% of DMAP taken orally was excreted as metabolites in the urine, 41% as glucuronide, 7% as sulfate, and 6% as thioethers. After i.v. administration the total of metabolites was somewhat higher, and the thioether proportion was 15%. The results indicate that DMAP is readily absorbed after oral administration but undergoes significant first pass effect in the liver. Therefore, the 4-fold i.v. dose must be administered orally to achieve the same ferrihemoglobin formation.     

Reduced Systemic Availability of an Antiarrhythmic Drug,Bidisomide, with Meal Co-administration: Relationship with Region-Dependent Intestinal Absorption

Purpose. The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide. Methods. Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model. Results. Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (–13%) was substantially smaller than the reduction (from –43% to –63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 ± 5.7% and 23.7 ± 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased C_max but not AUC, while viscous homogenized solid meals decreased both C_max and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC. Conclusions. The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.     

Pharmacokinetic characterization of ginsenoside Rh2, an anticancer nutrient from ginseng, in rats and dogs

The pharmacokinetic characteristics of ginsenoside Rh2, an anticancer nutrient, were analyzed in dogs and rats, including plasma kinetics, bioavailability, tissue distribution, plasma protein binding and excretion. The bioavailability of Rh2 is about 5% in rats and 16% in dogs. Multiple-dosing (7 days, 1 mg/kg bid) did not affect the pharmacokinetics in dogs. After oral dosing, Rh2 distributed mainly to the liver and gastrointestinal tissues in rats. In rats, the circulating fraction of Rh2 bound to plasma proteins was around 70%. The systemic clearance, however, was low – around 2 and 20 ml/min/kg in dogs and rats, respectively. Only 1% of dosed Rh2 were recovered in excreta of rats as the intact form after oral administration, while 30% was excreted unchanged in bile after i.v. dosing. We subsequently investigated the membrane permeability of Rh2 across Caco-2 cell monolayers, stability and elimination profiles in the gastrointestinal environment. Low membrane permeability (P_app(AP − BL): 1.91 × 10⁻⁸ cm/s), efflux transport (efflux ratio: 9.8), pre-systemic elimination (degradation in acidic condition; metabolism in intestine tissue and contents), as well as low solubility largely accounted for the low bioavailability of Rh2. Regarding the low solubility of Rh2, micronization of the dose almost doubled the rate of absorption in dogs. Preliminary metabolite profiling confirmed the presence of the deglycosidating product protopanaxadiol in rat feces. A possible metabolite in rat bile and a potential sulfate-conjugate in rat urine were also detected.     

Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment

Summary Milrinone, a new, nonglycosidic inotropic agent with peripheral vasodilating properties, was given as a single oral 5 mg dose to 7 healthy subjects, 7 patients with moderate renal impairment (CRI I, creatinine clearance 30–63 ml/min) and 7 patients with severe renal impairment (CRI II, creatinine clearance 9–29 ml/min). All except one of the patients with renal impairment had hypertension. The mean urinary recovery of milrinone was 82% in healthy subjects, the renal clearance was 288 ml/min and the plasma half-life (t_1/2) was 0.94 h. In CRI the mean plasma t_1/2 was prolonged (CRI I 1.78 h, CRI II 3.24 h). There was a significant linear relationship between creatinine clearance and the elimination rate constant, and between creatinine clearance and the renal clearance of milrinone. During the study day there was a tendency to a decrease in supine BP from 1 to 6–8 h after dosing, with the maximal decrease at 2–3 h (healthy subjects 118/71107/56, CRI 159/95136/79 mmHg). The same degree of change was seen in standing BP. A slight rise in standing HR was seen from 2–6 h after dosing. Changes in BP and HR are difficult to evaluate since the study was not placebo-controlled.The plasma elimination rate of milrinone was decreased in CRI and dose adjustment may be necessary. Placebo-controlled studies of milrinone in hypertensive patients would be required to validate its possible antihypertensive effect.