摘要:

AbstractIn this study the pharmacokinetics and pharmacodynamics of morphine‐3‐glucuronide (M3G) were investigated in rats after i.v. administration as a bolus dose (86.7 μmol kg−1) and as a constant rate infusion (2.9 μmol h−1) over 5 days. After the bolus dose, the clearance (Cl) was 12.1 ± 0.6 ml min−1* kg, the volume of distribution at steady state (Vss) 1.68 ± 0.89 1 kg−1, the half‐life of the first phase 13.2 ± 1.8 min and the halflife of the second phase 11.6 ± 7.7 h. After the constant rate infusion, Cl was 10.5 ± 1.7 ml min−1*kg. The antagonistic effect of M3G on the antinociceptive effect of a bolus dose of morphine (35 μmol kg−1) was tested during steady state concentrations of M3G on day 4 and to M3G naïve rats. No antinociceptive, hyperalgesic or withdrawal effects were observed as a result of M3G administration, but a significantly lower antinociceptive effect of morphine was found in the M3G infusion group compared to the control group. Systemically administered M3G antagonized the antinociceptive effect of morphine, but this cannot be the only explanation to the tolerance development observed aft

ISSN:0142-2782    

DOI:10.1002/bdd.2510140102

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

摘要:

AbstractSpecific and ultrasensitive reverse‐phase HPLC assays of the choleretic and biliary antispasmodic hymecromone (down to 0.05 ng ml−1) and its glucuronide, using fluorimetric detection, and sulfate metabolities using UV detection, were developed. Sodium salt solutions of 400 mg (over 3 min) and 800 mg (over 5 min) were infused i.v. into 6–8 normal human volunteers. The half‐life of the major rate constant averaged 28 ± 2 min (SE). Subsequently, less than 0.8 per cent of the dose was eliminated with terminal halflives of 70–359 min. The apparent volume of distribution of hymecromone, referenced to the total plasma concentration, averaged 20.8 ± 1.41 (Vc, central compartment volume) and 36.4 ± 2.11 (Vsssteady state volume). Hymecromone's total body clearance averaged 1413 ± 89 ml min−1. The pharmacokinetics of hymecromone were doseindependent. Only 0.3 ± 0.3 per cent unchanged hymecromone was renally excreted. Mostly dose‐independent glucuronidated drug (93 ± 4 per cent of the dose) was excreted in the urine; a smaller amount was renally excreted as the sulfate (1.4 ± 0.3 per cent of the dose). The oral bioavailability estimated from the relative areas under the hymecromone plasma concentration—time curves following oral and i.v. administration of hymecromone to six volunteer subjects showed no dose‐dependence and was 1.8 ± 0.6 per cent. However, an anomalousc.200 per cent of the glucuronide produced by i.v. hymecromone was produced from orally administered hymecromone as determined from the ratio of the AUC values of glucuronide obtained after peroral and i.v. administration of the same dose of hymecromone to demonstrate a high first‐pass effect and impl

ISSN:0142-2782    

DOI:10.1002/bdd.2510140103

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

摘要:

AbstractDespite the usefulness of angiotensin converting enzyme (ACE; EC 3.4.15.1) inhibitors for patients with renal insufficiency, some hesitation has been exercised in applying ACE inhibitors to the treatment of such patients because most ACE inhibitors are excreted mainly into the urine. In this context, development of an ACE inhibitor which is excreted into the bile has been sought.The pharmacokinetic properties of the novel ACE inhibitor, temocapril hydrochloride (temocapril HCl; CS‐622), were investigated in six healthy volunteers. This drug is excreted mainly into the bile in animal studies. Temocapril HCl was given in a single dose of 0.5, 1.0, and 2.0 mg, and 36, 44, and 38 per cent of the administered drug was excreted in the feces and 17, 19, and 24 per cent in the urine as the de‐esterified active diacid form (the diacid metabolite) within 48 h, respectively. The plasma ACE activity was markedly inhibited. No abnormal clinical findings suggestive of side‐effects were observed. Thus, from the pharmacokinetic standpoint, temocapril HCl is expected to be a useful drug for patients with renal dysfun

ISSN:0142-2782    

DOI:10.1002/bdd.2510140104

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of the following two polyesteric prodrugs of valproic acid (VPA) have been investigated: 1,4‐butanediol divaiproate (BDV) and glyceryl trivalproate (GTV). In addition, the anticonvulsant activity of these compounds has been evaluated and compared to that of VPA and valpromide (VPD). Valproic acid, and its two esteric derivatives were administered intravenously to six dogs at an equivalent dose (400 mg VPA) and their pharmacokinetics investigated. In the case of BDV, the biotransformation to VPA was complete, but in the case of GTV, it was only partial. Of the two investigated esteric prodrugs of VPA, only BDV demonstrated anticonvulsant activity and showed less neurotoxicity than VPA and VPD, and therefore had a better protective index. The anticonvulsant activity is explained on pharmacokinetic and pharmacodynamic grounds due to its complete conversion to VPA and the possible synergism in anticonvulsant activity between VPA and 1,4‐butaned

ISSN:0142-2782    

DOI:10.1002/bdd.2510140105

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe kinetics of conversion of methenamine to the active form formaldehyde were studied in pooled urine samples at 37° in the pH range 4.9–6.5. Using a method for the determination of both formaldehyde and unhydrolyzed methenamine, the rate of formaldehyde formation in urine was found to be apparent first order and was pH dependent. Bactericidal concentrations of formaldehyde (>28 μg ml−1) were achieved in 3 h in urine of pH 6.0 containing methenamine at 750 μg ml−1. There was no difference in thein vitrorate of conversion of methenamine to formaldehyde between the urine collected from normal subjects and the urine from subjects administered ascorbic acid. The rates of degradation of the mandelate and hippurate salts in buffer systems of various pH values did not differ significantly from those of methenamine base in urine adjusted to the same pH. The half‐life of methenamine conversion to formaldehyde increased approximately 20 times from 20 h at pH 5.0 to about 400 h at pH 6.5. The data suggest that unless the urine is maintained below pH 6 only a small fraction of methenamine would be converted daily to formaldehyde and, thus, may explain the need for large doses of this drug i

ISSN:0142-2782    

DOI:10.1002/bdd.2510140106

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

摘要:

AbstractA method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.

ISSN:0142-2782    

DOI:10.1002/bdd.2510140107

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510140108

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

摘要:

AbstractThe blood to plasma ratio of the antimalarial mefloquine has been reported to be close to 1, while other reports indicate extensive accumulation in erythrocytes. This apparent contradiction has been resolved by a quantitative examination of the compensating effects of plasma protein binding of mefloquine which almost exactly matches the extent of mefloquine accumulation in erythrocytes. The observed blood to plasma ratio of about 1 arises as the result of a balance between extensive red cell uptake and extensive plasma protein binding. Some pharmacokinetic implications of the distribution of mefloquine within blood are outlined.

ISSN:0142-2782    

DOI:10.1002/bdd.2510140109

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510140110

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510140101

出版商:John Wiley&Sons, Ltd.    

年代:1993

数据来源: WILEY