The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes.

1. The pharmacokinetics of [R]-leucovorin ([R]-LV), [S]-leucovorin ([S]-LV) and the circulating metabolite [S]-5-methyltetrahydrofolate ([S]-5-MTHF) were studied after administration of racemic LV and [S]-LV in 21 subjects. 2. After intravenous infusion of 600 mg m-2 rac-LV (group 1, n = 7) or 300 mg m-2 [S]-LV (group 3, n = 7), the decay of [S]-LV in plasma was biexponential with a distribution half-life of 0.8 to 1 h and an elimination half-life of 11 to 23 h. When rac-LV was administered as a 2 h i.v. infusion (400 mg m-2) following a loading dose of 200 mg m-2 (group 2, n = 7), the plasma concentrations of [R]-LV and [S]-5-MTHF decayed monoexponentially with mean (+/- s.d.) half-lives of 10 +/- 3 h and 7 +/- 2 h, respectively. 3. The AUC of [S]-5-MTHF was significantly higher after infusion of 300 mg m-2 [S]-LV than after infusion of 600 mg m-2 rac-LV (83 +/- 22 micrograms ml-1 h vs 53 +/- 22 micrograms ml-1 h; P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of midazolam in the enflurane-anesthetized dog

Midazolam (Mid) is widely used as an anesthetic adjunct. To test its anesthetic effect vs. concentration relationships, it is desirable to establish stable and predictable Mid concentrations in plasma (and brain). Therefore, the pharmacokinetics of Mid in the enflurane-anesthetized dog were determined, and the ability of Mid to reduce the enflurane concentration required for anesthesia was measured and correlated with the Mid concentration in plasma [MID]. Mongrel dogs (n = 9) were anesthetized with enflurane and the enflurane EC50 (MAC--the end-tidal concentration at which one-half of the dogs respond to the noxious stimulation of clamping of the tail, and one-half do not) was determined. Group 1 (n = 5) received Mid 2.5 mg/kg iv over 60 sec. Plasma for determination of [MID] was collected and the enflurane EC50 was determined repeatedly over the 7-8-hr period following injection. Based on the pharmacokinetic parameters determined for Group 1, dogs in Group 2 (n = 4) received Mid as a continuous infusion of 21 micrograms kg-1 min-1 for 5 hr accompanied by an initial loading dose (3 mg/kg infused over 20 min) designed to produce a stable [MID] of 1000 ng/ml in plasma. Enflurane MAC and [MID] were determined regularly during the infusion and for 6 hr after discontinuation of the infusion. There were no important differences in the pharmacokinetic parameters determined for Group 1 vs. Group 2: t1/2,z = 98 +/- 5 vs. 95 +/- 10 min (mean +/- SEM); V = 3.94 +/- 0.27 vs. 2.98 +/- 25 L/kg; Cl = 28.5 +/- 3.1 vs. 22.3 +/- 1.1 ml kg-1 min-1, respectively. When administered as a continuous intravenous infusion (Group 2), [MID] remained stable at 949 +/- 53 ng/ml for more than 5 hr. The enflurane EC50 was reduced by 55% and the reduction remained stable during the 5 hours of Mid infusion. After a single iv bolus dose or after discontinuation of the continuous infusion, the degree of enflurane EC50 reduction diminished toward the control (i.e., enflurane alone) value as [MID] declined. Mid-azolam's pharmacokinetics and plasma concentration vs. effect relationships have been determined to be consistent under two different experimental conditions.     

The metabolic chiral inversion of 2-phenylpropionic acid in rat, mouse and rabbit

The metabolic chiral inversion of the 2-arylpropionic acids has been investigated in laboratory animals, using the simplest congener, 2-phenylpropionic acid, as a model compound. The chiral inversion was found to occur after administration of the racemate to the rat and rabbit, but not in the mouse. The formation of the ester glucuronide was enantioselective for the S-(-)-isomer in the rat and mouse, but showed no stereoselectivity in the rabbit. [corrected] In the rat, the extent of inversion from R-(-) to S-(+) was greater at a dose of 30 mg/kg than at 150 or 300 mg/kg. The enantiomeric composition of the acid in urine was the same when the racemate was given orally or by i.p. injection. When the R-(-)isomer was given to rats, some 30% of the excreted acid was in the S-(+)-form, but when the S-(+)-isomer was given, the inversion was much less evident. In this case, the S/R ratio of the excreted phenylproprionic acid was ca 9:1. Following the administration of the racemate to rats, the plasma elimination half-life of the R-(-)-form was shorter (3.0 vs 4.8 hr for the S-(-)-isomer); this was due to its considerably greater plasma clearance (65.9 vs 43.6 micrograms/ml hr), since the volumes of distribution of the enantiomers were the same. The S/R ratio of 2-phenylpropionic acid in plasma rose progressively with time, from 1:1 in the dose solution to 2.1:1 at 8 hr.     

Severe 5-fluorouracil toxicity associated with a marked alteration of pharmacokinetics of 5-fluorouracil and its catabolite 5-fluoro-5,6-dihydrouracil: a case report

OBJECTIVE: To describe the altered pharmacokinetics of 5-fluorouracil (5-FU) and its major catabolite 5-fluoro-5,6-dihydrouracil (5-FDHU) in a 52-year-old woman affected by a severe 5-FU toxicity. METHODS: Toxicities were rated according to World Health Organization. 5-FU and 5-FDHU plasma concentrations and dihydropyrimidine dehydrogenase (DPD) activity of peripheral blood mononuclear cells (PBMC) were measured by HPLC analysis. RESULTS: After a single cycle of 5-FU therapy the patient developed grade 4 diarrhea and stomatitis, grade 3 vomiting, neutropenia, and dermatitis. Compared to a control population, 5-FU AUC, elimination half-life, and C(max) were markedly increased (24.75 vs. 9.25 +/- 0.63 h microg/ml, >5 vs. 0.36 +/- 0.05 h, and 58.54 vs. 37.2 +/- 4.03 microg/ml, respectively) whereas systemic clearance was decreased (12 vs. 51.29 +/- 2.97 l/h/m2); also 5-FDHU AUC (3.3 vs. 12.35 +/- 0.7 h microg/ml) and C(max) (3.4 vs. 4.56 +/- 0.15 microg/ml), which was reached with delay, were reduced. Surprisingly, the PBMC DPD activity (110.8 pmol/min/mg protein) and urinary uracil (68.32 micromol/g urinary creatinine) were within normal range. CONCLUSIONS: Our results show the altered 5-FU and 5-FDHU pharmacokinetics in a severe 5-FU toxicity case due to an impairment of the hepatic DPD activity and suggest the necessity of a pharmacological evaluation of 5-FU treated patients.     

Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease

1. Methylenetetrahydrofolate reductase (MTHFR) is a regulating enzyme in folate-dependant homocysteine remethylation, because it catalyses the reduction of 5,10 methylenetetrahydrofolate to 5-methyltetrahydrofolate (5-MTHF). 2. Subjects homozygous for the 677C --> T mutation in the MTHFR enzyme suffer from an increased cardiovascular risk. It can be speculated that the direct administration of 5-MTHF instead of folic acid can facilitate the remethylation of homocysteine in methionine. 3. The aim of this study was to determine the pharmacokinetic properties of orally administered 6[R,S] 5-MTHF versus folic acid in cardiovascular patients with homozygosity for 677C --> T MTHFR. 4. This is an open-controlled, two-way, two-period randomised crossover study. Patients received a single oral dose of either 5 mg folic acid or 5 mg 5-MTHF in each period. The concentrations of the 6[S] 5-MTHF and 6[R] 5-MTHF diastereoisomers were determined in venous blood samples. 5. All pharmacokinetic parameters demonstrate that the bioavailability of 5-MTHF is higher compared to folic acid. The peak concentration of both isomers following the administration of 6[R,S] 5-MTHF is almost seven times higher compared to folic acid, irrespective of the patient's genotype. However, at 1 week after the administration of a single dosage 6[R,S] 5-MTHF, we detected 6[R] 5-MTHF following the administration of folic acid, indicating storage of this isomer in the body. 6. Our results demonstrate that oral 5-MTHF has a different pharmacokinetic profile with a higher bioavailability compared to folic acid, irrespective of the patient's genotype. Detrimental effects of the storage of high levels of the non-natural isomer 6[R] 5-MTHF cannot be excluded.     

Enantioselective disposition and protein binding of [(5,6-dichloro-9a-propyl-3-oxo-2,3,9,9a-tetrahydro-1-H-fluoren-7 -yl)-oxy] acetic acid, a new cerebral antiedemic agent, in rats

[(5,6-Dichloro-9a-propyl-3-oxo-2,3,9,9a-tetrahydro-1-H-fluoren-7-y l)-oxy] acetic acid (DPOFA) is an agent capable of reducing the swelling of astroglial cells in brain tissues. In vitro studies have demonstrated that the (R)-(+)-form of DPOFA is more effective than its (S)-(-)-form in inhibiting tissue swelling. The purpose of this study is to compare the elimination kinetics of the enantiomers. A new stereoselective HPLC procedure was developed for the simultaneous quantitation of (R)-(+)- and (S)-(-)-enantiomers in plasma and bile samples. After iv administration of the racemic mixture (40 mg/kg), rats cleared the (R)-(+)-enantiomer more rapidly than the (S)-(-)-isomer; time-averaged total plasma clearances were 8.88 +/- 0.55 and 4.20 +/- 0.70 ml/min/kg (mean +/- SD), respectively. Similar results were observed when the individual isomers were administered (20 mg/kg iv). Both (R)-(+)- and (S)-(-)-enantiomers were highly bound to plasma protein. The (R)-(+)-isomer had a higher unbound fraction (2%) than did the (S)-(-)-enantiomer (0.8%). The intrinsic clearance of unbound drug for (R)-(+)- and (S)-(-)-enantiomers were 434 +/- 27 and 490 +/- 84 ml/min/kg, respectively, suggesting that the differences in the elimination of the enantiomers in rats were attributable to stereoselectivity in plasma protein binding rather than to enzyme activity. In vitro studies with isolated hepatocytes supported the hypothesis that there was no stereoselectivity in metabolism of the enantiomers.     

Analysis and stereoselective metabolism after separate oral doses of tocainide enantiomers to healthy volunteers

The potential of stereoselective metabolism of tocainide was studied in six healthy volunteers after separate oral administration of the pure enantiomers in solution. A method was developed to convert the N-carbamoylglucuronide of tocainide in plasma and urine by base treatment to a hydantoin derivative which after extraction and silation was analysed by selected ion monitoring using a deuterated internal standard. Analytical problems concerning side-reactions during derivatization of the conjugate are discussed. The peak plasma levels of the enantiomers, observed at less than or equal to 2 h after dosing, were similar but plasma clearances and terminal half-lives were different after oral administration of (R)-tocainide (195.5 +/- 20.1 ml min-1 and 9.7 +/- 0.8 h) and (S)-tocainide (110.2 +/- 10.5 ml min-1 and 14.5 +/- 1.7 h). Over 0-96 h the averaged urinary recovery of (R)-tocainide was 36 per cent and of (S)-tocainide 50 per cent. Stereoselective metabolism was a likely mechanism for the observed differences as the urinary recovery of the conjugate formed from (R)-tocainide differed substantially from that of (S)-tocainide (45 vs 1.2 per cent of given dose). Plasma t1/2 of the (R)- and (S)-conjugate were 9.9 and 18.7 h, respectively, indicating formation rate limited kinetics of the metabolite. The renal clearances of the conjugates were not significantly different (131 vs 97 ml min-1).     

Differential metabolism of fenvalerate and granuloma formation. II. Toxicological significance of a lipophilic conjugate from fenvalerate

Male mice of the ddY strain were fed a diet containing the [2S, alpha S]-, [2S, alpha RS]-, [2R, alpha S]-, and [2R, alpha R]-isomers of fenvalerate. Microgranulomatous changes were observed only in mice treated with the [2R, alpha S]-isomer at 125 and 1000 ppm for 1, 2, or 3 months. In contrast, the changes did not occur in mice treated with the [2R, alpha R]-isomer under the same conditions. Feeding of the [2S, alpha S]- and [2S, alpha RS]-isomers for 1 year did not cause the microgranulomatous changes at 500 or 1000 ppm. To clarify the causative agent of granuloma formation, cholesterol ester of 2-(4-chlorophenyl)isovaleric acid (CPIA), a lipophilic conjugate from the [2R, alpha S]-isomer of fenvalerate, was injected iv into ddY mice. Microgranulomatous changes were observed in the liver of mice treated with the [2R]-, [2S]-, or [2RS]-CPIA-cholesterol ester 1 week after a single treatment of 1, 10, or 100 mg/kg, as well as in liver of mice treated with a single dose of 10 or 30 mg/kg of the [2R]-CPIA-cholesterol ester and kept up to 26 weeks afterward. Histochemistry and microscopic autoradiography of the liver of mice demonstrated the presence of tritium derived from 3H-labeled[2R]-2-(4-chlorophenyl)isovalerate and cholesterol. Histochemistry also was positive for cholesterol ester in livers of mice treated with the [2R, alpha S]-isomer of fenvalerate. These results lend support for the hypothesis that CPIA-cholesterol ester is the causative agent of microgranulomatous changes induced by fenvalerate.     

Comparison of the antidiarrheal effects of zaldaride maleate and its optical isomers in rats

Zaldaride maleate (ZAL), a calmodulin inhibitor, that ameliorates secretory diarrhea in rodents, has a racemic structure. In this study, we compared the antidiarrheal and antisecretory effects of ZAL and its optical isomers, R(-)-isomer and S(+)-isomer, in rats. In Ussing chamber experiments, the inhibitory action of ZAL on acetylcholine-induced ion transport in the rat colonic mucosa was equipotent for both optical isomers, with IC50 values of approximately 3--4 micromol/l. In castor-oil-induced diarrhea, ZAL and its S(+)-isomer inhibited the incidence of diarrhea, whereas the R(-)-isomer had no effect. In 16,16-dimethyl prostaglandin E2-induced diarrhea, ZAL, the S(+)-isomer and the R(-)-isomer significantly ameliorated diarrhea at doses of 30, 10 and 30 mg/kg (p.o.), respectively; the ED50 values were 25, 10 and above 30 mg/kg (p.o.), respectively. The pharmacokinetic parameters after administration of 30 mg/kg (p.o.) of each compound were as follows: ZAL (Cmax: 378 ng/ml, AUC0-12: 1650 ng-h/ml); S(+)-isomer (Cmax: 565 ng/ml, AUC0-12: 2230 ng-h/ml) and R(-)-isomer (Cmax: 271 ng/ml, AUC0-12: 613 ng-h/ml) (mean, N=4). In conclusion, despite the fact that the antisecretory actions of ZAL and its optical isomers are the same, the antidiarrheal actions of ZAL and its S(+)-isomer are more potent than that of the R(-)-isomer. The antidiarrheal actions of ZAL and its optical isomers may be related to plasma levels.     

普罗帕酮经转人肝CYP3A4基因中国仓鼠CHL细胞代谢的立体选择性

目的:研究普罗帕酮(PPF)经人肝CYP3A4代谢的立体选择性。方法:以转人肝CYP3A4基因中国仓鼠肺细胞CHL的S_9为酶源,考察了PPF消旋体及单个对映体在高、低底物浓度时的经时孵育代谢。对映体抑制试验用于考察对映体之间的相互作用。并进行了单个对映体的酶动力学试验。结果:PPF消旋体高底物浓度(400mg/L)时的代谢无立体选择性,低底物浓度(10mg/L)时R(-)-体代谢快于S( )-体(R>S);单个对映体孵育时在高底物浓度(200mg/L)时的代谢呈现对S( )-体的立体选择性(S>R),低底物浓度(5mg/L)时呈现对R(-)-体的立体选择性(R>S)。S( )-PPF的V_(max)(μmol·mg~(-1)·min~(-1))大于R(-)-体(2.66±0.32 vs 1.71±0.19,P<0.01)。R(-)-PPF的K_m(μmol·L~(-1))小于S( )-体(73±11 vs 185±17,P<0.001)。R(-)-PPF对S( )-体有代谢抑制作用(IC_(50)=125μmol·L~(-1))。结论:PPF经人肝CYP3A4的代谢有底物浓度依赖性的立体选择性。高底物浓度时两对映体有相互作用,相互作用的结果导致立体选择性丧失。而低底物浓度时两对映体无相互作用,结果仍表现出R体代谢优先的立体选择性。     

[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C→T polymorphism of methylenetetrahydrofolate reductase

Background and purpose:

5,10-Methylenetetrahydrofolate reductase (MTHFR) is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C→T mutation of MTHFR reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid (FA) in women with the homozygous (TT) and wild-type (CC) 677C→T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and FA was evaluated by measuring plasma folate derivatives.

Experimental approach:

Healthy females (TT, n= 16; CC, n= 8) received a single oral dose of FA (400 µg) and [6S]-5-MTHF (416 µg) in a randomized crossover design. Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile [area under the curve of the plasma folate concentration vs. time (AUC)], maximum concentration (C_max) and time-to-reach-maximum (t_max) were calculated.

Key results:

AUC and C_max were significantly higher, and t_max significantly shorter for [6S]-5-MTHF compared with FA in both genotypes. A significant difference between the genotypes was observed for t_max after FA only (P < 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized FA in plasma occurs regularly following FA supplementation, but rarely with [6S]-5-MTHF.

Conclusions and implications:

These data suggest that [6S]-5-MTHF increases plasma folate more effectively than FA irrespective of the 677C→T mutation of the MTHFR. This natural form of folate could be an alternative to FA supplementation or fortification.     

静注卡介苗建立免疫性胰岛素抵抗模型

目的建立并考察卡介苗诱导的胰岛素抵抗动物模型。方法用正糖钳实验方法及其他生化检验方法测定卡介苗每鼠10 mg iv后大鼠血糖、葡萄糖耐量、血清TNF-α、胰岛素刺激的葡萄糖代谢速率及其他生化指标的变化。结果卡介苗iv后第2,4及8周,动物的葡萄糖耐量均受到损伤,胰岛素刺激的葡萄糖代谢速率显著下降,血清TNF-α含量升高。结论卡介苗iv可造成稳定的胰岛素抵抗模型,其造模机理可能与升高大鼠血清TNF-α含量有关。     

High clearance of (S)-warfarin in a warfarin-resistant subject.

A 30 year old black male required a 60 mg daily dose of warfarin to elicit a therapeutic anticoagulant response (normal warfarin dose 2.5-10 mg day-1; maximum 15 mg day-1). Hereditary warfarin resistance was suspected after compliance, diet, concurrent medication and any gastrointestinal disorder were eliminated as contributory causes. The disposition of vitamin K and vitamin K epoxide was examined in the propositus, his two sisters and 13 control black male subjects. Each subject was given an i.v. bolus dose (5 mg) of vitamin K prior to and after 2 weeks of warfarin therapy (5 mg day-1). The oral clearances of (S)- and (R)-warfarin were also measured in each subject during the last day of warfarin therapy. The mean (+/- s.d.) systemic clearance of vitamin K was similar in all subjects before (114 +/- 35 ml min-1) and after (112 +/- 40 ml min-1) warfarin therapy. The mean (+/- s.d.) AUC value for vitamin K epoxide was increased by warfarin treatment (6.5 +/- 5.4 micrograms ml-1 min before and 139 +/- 78 micrograms ml-1 min after) in all subjects. In the propositus, the oral clearance of (S)-warfarin (14.5 ml min-1) and the clearance ratio for (S)/(R)warfarin (2.6) differed by more than 7 standard deviations from the control group (4.3 +/- 1.1 ml min-1 and 1.2 +/- 0.2, respectively). In one sister of the propositus, the stereoselective disposition of warfarin was comparable with that of her brother ((S)-warfarin clearance = 16.2 ml min-1; and (S)/(R)-warfarin clearance ratio = 2.7).     

Hemodynamic effects of new angiotensin converting enzyme inhibitors during continuous angiotensin I infusion on conscious dogs

The effects of a 6 h infusion of 50 ng/kg.min angiotensin I on hemodynamic parameters were recorded in conscious male beagle dogs. Mean arterial pressure was elevated from 107 +/- 3 mmHg to 152 +/- 5 mmHg (mean +/- SEM, n = 5) within the first hour, followed by a slow decrease to 145 +/- 5 mmHg after 6 h. Cardiac output fell from 2.3 +/- 0.2 l/min to 1.6 +/- 0.2 l/min followed by an increase to 2.5 +/- 0.3 l/min. The peripheral resistance showed an exceeding increase from 2.9 +/- 0.2 mmHg.s/ml to 5.7 +/- 0.7 mmHg.s/ml and a slow decrease to 3.5 +/- 0.5 mmHg.s/ml. Heart rate was found to be decreased from 62 +/- 7 min-1 to 58 +/- 7 min-1 after 1 h. The angiotensin converting enzyme (ACE)-inhibitor enalapril caused a complete reduction of the angiotensin induced hypertension. Three new non-sulfhydryl containing ACE-inhibitors ((S)-N-[N-[1-[ethoxycarbonyl]-3-phenylpropyl]-L-alanyl]-N- [1-pyrrolidinyl]-glycine (REV 6207), (S)-N-[N-[1-[ethoxycarbonyl]-3-phenylpropyl]-L-alanyl]-N- [2-ethoxyethoxy]-glycine (REV 6134), (S)-N-[N-[1-[ethoxycarbonyl]-3-phenylporpyl]-L-alanyl]-N- [phenylmethyl]-glycine (REV 5975] were found to show a partial reduction of the angiotensin I effect. The duration of action which was found to be similar after oral and intravenous administration ranged from 83 +/- 33 min (n = 3) for REV 5975 to more than 360 min for enalapril. A correlation of the arterial pressure lowering and the percentage of the ACE-inhibition suggests that a considerable blood pressure effect can only be observed when more than about 80% of the ACE-activity is inhibited.     

Stereoselective pharmacokinetics and inversion of suprofen enantiomers in humans.

The stereoselective pharmacokinetics of suprofen enantiomers has been studied in humans by means of stable isotope-labeled pseudoracemate-diastereomer methodology. After a single oral dose of a near equimolar mixture of unlabeled-(R)-(-)- and [2H3]-(S)-(+)-suprofen [or unlabeled-(S)- and [2H3]-(R)-suprofen] to three healthy male subjects, the plasma concentrations of drug were determined by a stereospecific gas chromatography-mass spectrometry method. Racemic [2H7]suprofen was used as an internal standard. The method involved chiral derivatization with (S)-(-)-1-(naphthyl)ethylamine to form the diastereomeric amide. The plasma concentrations were consistently higher for the (R)-isomer than the (S)-isomer. No significant difference in the elimination half-life of the enantiomers was observed. An average of 6.8% of an administered dose of the (R)-isomer was stereospecifically inverted to the (S)-isomer. There was no measurable inversion of the (S)- to (R)-isomer. The present stable isotope-labeled pseudoracemate-diastereomer methodology has made it possible to evaluate the pharmacokinetics of each enantiomer, including the estimation of chiral inversion after administration of the racemic mixture.     

The pharmacokinetics and pharmacodynamics of ketamine in dogs anesthetized with enflurane

The plasma concentration vs. anesthetic effect relationships for ketamine are not well known. It is desirable to establish stable and predictable drug concentrations in plasma (and brain) in order to define such relationships. As a prelude to pharmacodynamic studies, we investigated ketamine pharmacokinetics in eight dogs anesthetized with enflurane and correlated ketamine concentration in plasma (KET) with its ability to reduce the enflurane concentration required for anesthesia (enflurane EC50: MAC--the end-tidal concentration at which half the dogs moved in response to clamping of the tail and half did not move). Four dogs (Group 1) received ketamine 10 mg/kg iv over 30 sec. Blood for determination of KET was collected repeatedly over the 5-h period following injection. Based on the pharmacokinetic parameters determined for Group 1, four dogs in Group 2 received ketamine as a continuous infusion of 300 micrograms.kg-1.min-1 for 5 hr accompanied by an initial loading dose (26 mg/kg administered over 20 min) designed to produce a stable KET of 20 micrograms/ml of plasma. Enflurane MAC and KET were determined regularly during the infusion and for 5 hr after discontinuation of the infusion. There were no significant differences in the following pharmacokinetic parameters determined for Group 1 vs. Group 2: t1/2 beta = 122 +/- 9 vs. 141 +/- 40 min (mean +/- SD) and CL = 18.1 +/- 5.9 vs. 13.9 +/- 2.5 ml.kg-1.min-1, respectively. When administered as a continuous infusion (Group 2), KET remained relatively stable at 22.1 +/- 4.6 micrograms/ml for 5 hr. The degree of MAC reduction remained relatively stable at 73% during the continuous infusion. Finally, the enflurane MAC reduction vs. KET was established over a wide range of plasma concentrations in 4 additional dogs (Group 3). This study determined that the pharmacokinetics of ketamine were consistent under two different experimental conditions and demonstrated the relationship between plasma concentration and anesthetic effect in the dog.     

Chronic vasopressin V(1A) but not V(2) receptor antagonism prevents heart failure in chronically infarcted rats

Evidence is increasing that therapeutic modulation of neurohormonal activation with vasopressin receptor antagonists via V(1A) and V(2) receptors may favourably affect prognosis of heart failure. This study was designed to compare in vivo hemodynamic effects of early treatment (1-21 days after infarction) with a V(1A) (SR-49059 or ((2S)1-[(2R3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide); 0.3 mg/kg/day) and a V(2) (SR-121463B or (1-[4-(N-tert-Butylcarbamoyl)-2-methoxybenzene sulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethyoxy)-cyclo-hexane]indol-2one,furmate; 0.5 mg/kg/day) receptor antagonist in myocardial infarcted rats, chronically instrumented for hemodynamic measurements. Left ventricular dysfunction in conscious myocardial infarcted rats, which was evidenced by a significantly decreased cardiac output (myocardial infarction: 70+/-3 vs. sham: 81 +/- 3 ml/min) and stroke volume (myocardial infarction: 190 +/- 10 vs. sham: 221 +/- 7 microl), was restored by the vasopressin V(1A) (81+/-2 ml and 224 +/- 5 microl, respectively) but not V(2) receptor antagonist. Improved cardiac output with the vasopressin V(1A) receptor antagonist resulted from an increased stroke volume at a reduced myocardial infarction induced tachycardia. In addition to the hemodynamic measurements, left ventricular hypertrophy and capillary density were determined, histologically measured as the cross-sectional area of Gomori-stained myocytes and Lectin-stained capillaries per tissue area, respectively. The observed left ventricular concentric hypertrophy (myocardial infarction: 525 +/- 38 vs. sham: 347 +/- 28 microm(2); P < 0.05) and reduced capillary density (myocardial infarction: 2068 +/- 162 vs. sham: 2800 +/- 250 number/mm(2); P<0.05) in the spared myocardium of myocardial infarcted rats, remained unaffected by the vasopressin V(1A) or V(2) receptor antagonist. Thus, chronic vasopressin V(1A) but not V(2) receptor blockade prevents heart failure in 3-week-old infarcted rats. Moreover, the improved cardiac function could not attributed to changes in left ventricular hypertrophy and/or capillary density.     

Differential metabolism of fenvalerate and granuloma formation. I. Identification of a cholesterol ester derived from a specific chiral isomer of fenvalerate

On a single po administration of the four chiral isomers of fenvalerate ([RS]-alpha-cyano-3-phenoxybenzyl [RS]-2-(4-cholorophenyl)isovalerate) to rats and mice at 2.5 mg/kg, the [2R, alpha S]-isomer showed relatively higher residues in all analyzed tissues as compared with the other three isomers. Similarly, this isomer showed higher tissue concentrations than other isomers when mice were fed a diet containing 500 ppm of the [2S, alpha S]-, and [2R, alpha R]-isomers for 2 weeks. The [2R, alpha S]-isomer produced a lipophilic metabolite in all the examined tissues on the basis of thin-layer chromatography analysis, but not for the other isomers. The amounts of lipophilic metabolite differed among tissues, being higher in adrenal, liver, and mesenteric lymph nodes following feeding to mice at 500 ppm of the [2R, alpha S]-isomer for 2 weeks. However, the amount did not increase proportionally with time and apparently reached a plateau within a rather short time. This metabolite was identified as cholesteryl [2R]-2-(4-chlorophenyl)isovalerate ([2R]-CPIA-cholesterol ester) on the basis of spectroanalysis and chromatographic behavior after purification on silica gel, Florisil, thin-layer, and high-pressure liquid chromatography. The presence of the same metabolite also was indicated in rat tissues. The CPIA-cholesterol ester was rapidly formed and found in all the analyzed tissues of mice 1 hr after a single po administration of the [2R, alpha S]-isomer.     

Inhibition of endothelial-bound angiotensin converting enzyme, in vivo.

1. We determined apparent Ki constants of two inhibitors, captopril and CL242,817, for pulmonary endothelial-bound angiotensin converting enzyme (ACE) in anaesthetized rabbits. [3H]-benzoyl-Phe-Ala-Pro was used as the substrate. The apparent kinetic parameters Km and Amax (product of Vmax and microvascular plasma volume) were measured, as was the ratio (Amax/Km) (measured under first order reaction conditions) before and 30s after the i.v. administration of captopril 10 nmol kg-1 or CL242,817, 35 nmol kg-1. 2. Under mixed order reaction conditions, ([S] greater than or equal to Km), apparent Km values increased from 12.2 +/- 1.9 microM to 32.9 +/- 3.3 microM (P less than 0.05) in the captopril-treated rabbits and from 9.3 +/- 2.3 microM to 45.8 +/- 9.8 microM (P less than 0.05) in the CL242,817-treated rabbits, indicative of competitive inhibition. However, apparent Amax values decreased from 10.3 +/- 2.1 to 4.5 +/- 0.8 mumol min-1 (P less than 0.05) and 8.9 +/- 1.7 to 4.8 +/- 0.5 mumol min-1 (P less than 0.05), respectively. 3. Under first order reaction conditions ([S] much less than Km), the Amax/Km ratio decreased from 763 +/- 100 to 125 +/- 38 ml min-1 (P less than 0.05) and 1009 +/- 149 to 126 +/- 44 ml min-1 (P less than 0.05) in the captopril- and CL242,817-treated groups respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers

AIMS: To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administration of two doses (100 and 300 mg) of fantofarone. METHODS: A placebo-controlled, randomized, double-blind and crossover study was performed in six healthy volunteers. SR 33671 plasma concentrations (C, ng ml-1 ) and effects (E) on heart rate (HR, beats min-1 ), PR interval duration (ms), brachial artery flow (BAF, ml min-1 ) and brachial vascular resistance (BVR, mmHg s ml-1 ) were determined repeatedly after drug intake. Haemodynamic effects were expressed as percent changes from initial values. Bi-exponential (pharmacokinetics), and linear [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cgamma/(CEgamma50+Cgamma ), for haemodynamic effects] models were fitted to individual data. RESULTS: Peak plasma concentrations and areas under the curve up to 24 h were (mean+/-s.d.) 16+/-10 ng ml-1 and 157.50+/-89.13 ng ml-1 h, and 63+/-11 ng ml-1 and 535.50+/-135.11 ng ml-1 h, after 100 and 300 mg, respectively. Terminal half-life was approximately 4 h. For pharmacodynamics, we obtained: S=-0.201+/-0.057 beats min-1/ng ml-1 for HR, S=0.526+/-0.114 ms/ng ml-1 for PR interval duration, Emax=42+/-6%, CE50=8.8+/-7.2 ng ml-1 and gamma=2.2+/-1.5 for BAF, and Emax=-28+/-4%, CE50=5.8+/-5.1 ng ml-1 and gamma=3.4+/-1.8 for BVR. At a SR 33671 concentration of 15 ng ml-1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats min-1 and PR interval duration is increased by less than 8 ms. CONCLUSIONS: Fantofarone is able to induce submaximal peripheral vasodilating effects at doses that are devoid of any clinically significant cardiac effect.