摘要:

AbstractThe pharmacokinetics of a series of novel cyclic, non‐peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC90, values of 0.03–1.0 μM (0.017–0.76 μg mL−1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21–1.88 μg mL−1were detected within 1 h of oral administration of 10 mg kg−1of the compounds. The elimination half‐lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 μg mL−1and 48%, 1.07 μg mL−1and 16%, and 1.48 mg mL−1and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC90for inhibition of viral replication after single doses of 10 mg kg−1in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatmen

ISSN:0142-2782    

DOI:10.1002/bdd.2510150702

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe stereoselective disposition and metabolic inversion of ibuprofen were studied in 12 healthy subjects under conditions of competitive and non‐linear plasma protein binding. Each subject received each of four oral treatments according to a Latin‐square design: 300 mg R(−)‐ibuprofen, 300 mg S(+)‐ibuprofen, 300 mg R(−)‐ + 300mg S(+)‐ibuprofen, and 300 mg R(−)‐ + 600 mg S(+)‐ibuprofen. For a given treatment, the partial clearance of S(+)‐ibuprofen was greater than that of R(−)‐ibuprofen for all stereoisomeric drug species. Likewise, the unbound partial clearances of S(+)‐ibuprofen were greater for most stereoisomeric drug species. There was also less difference among treatment groups when partial clearances were referenced to unbound as opposed to total plasma concentrations of enantiomer. The unbound intrinsic clearance and fractional inversion of R(−)‐ibuprofen were unchanged across the four treatments, and chiral inversion was systemic, averaging 69%. In conclusion, stereoselective differences exist for the partial and composite clearances of R(−)‐ and S(+)‐ibuprofen even when corrected for differences in plasma protein binding. However, differences among treatment groups for a particular elimination pathway are largel

ISSN:0142-2782    

DOI:10.1002/bdd.2510150703

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractCefoperazone is a semisynthetic cephalosporin antibiotic containing a piperazine side chain, which results in antipseudomonal activity. Unlike the other cephalosporins, it is mainly cleared by the liver (60–80%) and it may be more sensitive to changes in the liver function and/or plasma protein binding than other cephalosporins, which are not primarily cleared by the liver. In order to study the influence of chronic lobular hepatitis on the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 normal, healthy volunteers and 16 subjects with chronic lobular hepatitis. In each volunteer or patient, a novel galactose single‐point (GSP) method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were also performed as a measure of residual liver function. Cefoperazone was administered intravenously over a period of 3–5 min. Blood and urine samples were collected at appropriate intervals after drug administration and stored at −30°C until high‐pressure liquid chromatographic (HPLC) analysis.The cefoperazone hepatic clearance, mean residence time, and renal clearance in hepatitis patients were significantly different from those of normal healthy volunteers, whereas the plasma protein binding was unaltered between the two groups. Urinary excretion of cefoperazone showed a highly significant increase in patients, 23.95 ± 5.06% and 37.54 ± 13.61% for normal men and hepatitis patients respectively. Hepatic clearance and fraction excreted in urine significantly correlated with values of GSP and MGEC respectively (p<0.05). These results suggest (i) cefoperazone kinetics was significantly altered in patients with chronic lobular hepatitis; (ii) GSP, a novel simple, clinically useful quantitative liver function test, can predict the cefoperazone hepatic clearance in patients with liver

ISSN:0142-2782    

DOI:10.1002/bdd.2510150704

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractA study was carried out in 14 cancer patients to assess the relative bioavailability of two oral formulations of navelbine. A single 130 mg oral dose of the drug was given according to a randomized two‐way crossover design as two capsules: one contained the drug in powder (formulation A, reference); another contained the drug in solution (formulation B). A 7 d washout period separated each dose. Navelbine was rapidly absorbed after administration of either formulation and exhibited a biphasic concentration decay pattern. The peak plasma level was reached within 2 h of administration in most patients. Formulation B resulted in better naveibine absorption with respect to peak plasma concentration (Cmax) and area under the plasma concentration—time curves (AUC) than did formulation A as ascertained by analysis of variance (ANOVA). The relative bioavailabilities (solution versus powder) were, respectively, 286.0% and 268.0% as estimated from experimental (0–72 h) and extrapolated (0

ISSN:0142-2782    

DOI:10.1002/bdd.2510150705

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractChlorzoxazone is 6‐hydroxylated by cytochrome P450 2E1 (CYP 2E1), which bioactivates many toxic and carcinogenic molecules. Seventeen volunteers of varying age, ethnicity, and gender received a 250 mg tablet of chlorzoxazone and their blood and urine were sampled frequently for 8 h.V/F= 42 ± 21 L and CL/F= 412 ± 120 mL min−1. Comparison of these values with a study by other investigators using a suspension dosage form suggested that relativeFtablet± 0.7. The fraction excreted in the urine as 6‐hydroxychlorzoxazone (f2,6‐OH) was 0.39 ± 0.20 and that portion of the total CL accounted for by CYP 2E1‐mediated metabolism (CL6‐OH) was 163 ± 95 mL min−1. Thus, whileV/Fand CL/Fvaried by factors of less than five,fe,6‐OHvaried 16‐fold and CL6‐OHvaried 28‐fold. These results suggested that there was considerable inter‐individual variability in the metabolism of chlorzoxazone to 6‐hydroxychlorzoxazone. This variability will significantly affect the construction of physiologically based pharmacokinetic models that use the 6‐hydroxylation of chlorzoxazone as a marker for a

ISSN:0142-2782    

DOI:10.1002/bdd.2510150706

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

Abstract(i)The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin.(ii)Six groups of five patients participated in the study. The first three groups (A–C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D–F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously.(iii)Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients.(iv)Largeinter‐individual variation in bone concentration was observed.(v)The bone concentrations of IV cefuroxime were higher (1500 mg,p= 0.0057; 1000 mg,p= 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose depe

ISSN:0142-2782    

DOI:10.1002/bdd.2510150707

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics and renal excretion of a trichothecene mycotoxin, verrucarol, were studied in six mongrel dogs following IV administration (0.4 mg kg−1).The fraction of verrucarol excreted intact in the urine ranged from 0.9% to 2.7% of the administered dose. The fraction of verrucarol metabolites excreted in the urine was 32–60% for verrucaryl glucuronides and 32–47% for verrucaryl sulphates. These urinary conjugated metabolites were analyzed quantitatively following their enzymatic hydrolysis. The half‐life of verrucarol calculated from the urinary data of its conjugated metabolites was not significantly different from the half‐life calculated from the plasma data of the parent

ISSN:0142-2782    

DOI:10.1002/bdd.2510150708

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetic (PK) characteristics of KNI‐272, a potent and selective HIV‐1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI‐272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI‐272, were examined. After IV administration of 10.0 mg kg−1KNI‐272, the mean terminal elimination half‐life,t1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CLtot, was 15.1 ± 1.2 mL min−1and the distribution volume at steady state,Vd,ss, was 3790±280 mL kg−1. On the other hand, after 1.0mg kg−1IV administration,td,ss, was 3.04±0.11 h, CLtotwas 15.9±0.2mL min−1, andVd,sswas 6950±600 mL kg−1. The PK parameters of KNI‐272 after IV administration showed that the disposition of KNI‐272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg−1. Using an equilibrium dialysis method, the plasma binding of KNI‐272 was measuredin vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL−1, 0.888 ± 0.008 μg mL−1, and 0.470±0.55 μg mL−1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg−1dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg−1dose, respectively. The renal clearance (CLR) and the biliary clearance (CLB) were calculated to be 0.191 and 0.256mL min−1for 1.0mg kg−1, and 0.0248 and 0.215 mL min−1for 10.0 mg kg−1, respectively. When comparing these values with the CLtotvalues, the

ISSN:0142-2782    

DOI:10.1002/bdd.2510150709

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510150701

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY