摘要:

AbstractThe pharmacokinetics and pharmacodynamics of adinazolam and N‐demethyladinazolam (NDMAD) were evaluated in twelve healthy non‐smokers (NS) and twelve smokers (S, ⩾ 20 cigarettes/day) following a single 60 mg dose of adinazolam mesylate sustained‐release tablets in an open‐label, parallel‐group design. Venous blood samples were collected for up to 36 h following drug administration and assayed for adinazolam and NDMAD by HPLC. Urine samples were also collected and assayed for NDMAD by HPLC. Psychomotor performance was measured using the Neurobehavioral Evaluation System. No significant differences were observed in adinazolam oral clearance (51.8±25.8versus48.2±14.01 h−1) or peak adinazolam plasma concentrations (Cmax) (93.3±31.8versus90.4±18.0 ng ml−1) between groups. NDMAD AUC (2541.457versus2798±447 ng h ml−1) andCmax(173±30.3versus175±26.9 ng ml−1) did not differ significantly between groups. NDMAD renal clearance was significantly lower in smokers than non‐smokers (8.7±0.7versus10.7±2.71 h−1;p<0.05), but the clinical significance of this observation is unclear. Marginally significant differences were seen between groups in the symbol‐digit substitution and digit span (forward) tasks. The results suggest that smoking has little effect on adinazolam and NDMAD pharmacokinetics or psychomotor effects but that smoking may slightly

ISSN:0142-2782    

DOI:10.1002/bdd.2510150402

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractA method is described for calculating the mean transit time and distribution rate parameters of a generated primary metabolite undergoing linear distribution and linear or non‐linear central elimination, and of catenary metabolites with any precursor order. It is also applicable to a drug and its interconversion metabolite and does not require separate administration of the metabolite. The method allows steady‐state volume of distribution and distribution clearance of a metabolite to be calculated, provided that the central volume of distribution of the metabolite is known. An algorithm and computer program to implement the proposed method are presented. The calculations require the plasma concentrationversustime curves of the metabolite and its precursor. The method is applied to both published and simulated d

ISSN:0142-2782    

DOI:10.1002/bdd.2510150403

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractValues forVmaxandKmdetermined during thein vitrometabolism of a xenobiotic to a known metabolite by a specific human isozyme of cytochrome P450 (P450) were used to predict the hepatic clearance (CLH) of the xenobiotic to that metabolite. The calculated CLHvalues were then compared to literature values of clearance (CL) to the same metabolite obtained during pharmacokinetic studies in humans. For the 6‐hydroxylation of chlorzoxazone (P450 2E1) the predicted and actual clearances were 110±77 mL min−1and 110 mL min−1, respectively. For the 6β‐hydroxylation of cortisol, the deethylation of lidocaine (two studies), and the oxidation of nifedipine (all P450 3A3/4) the values were 13±15 mL min−1and 13 mL min−1; 758±282 or 829±283 mL min−1and 875 mL min−1; and 284±176 mL min−1and 294 mL min−1, respectively. An increase to 72±25 mL min−1in the CLHof cortisol to 6β‐hydroxycortisol was calculated following rifampicin treatment. Finally, the polymorphic nature of the metabolism (P450 2D6) of mexiletine was confirmed. The usefulness of the method an

ISSN:0142-2782    

DOI:10.1002/bdd.2510150404

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of azosemide were evaluated simultaneously using both arterial and venous plasma data in six rabbits after a rapid 5 s intravenous bolus dosing. Initial arterial to venous ratios at 5 s after injection were the highest with values of 81.1, 67.3, 58.7, 530, 2660, and 10.5 for rabbits 1–6, respectively. Both curves decayed, paralleling each other at the terminal phase, with the venous levels higher than the arterial levels by 15.3, 31.9, 34.1, 40.7, 30.5, and 16.5% for rabbits 1–6, respectively. An exponential term with a negative coefficient was used to account for the short and steep rising phase of venous plasma levels after injection. Detailed analysis showed significant differences in various pharmacokinetic parameters, such as initial volume of distribution, apparent volume of distribution at steady state, and mean residence time based on arterial or venous data. A plot of 1/Q(urine flow rate) versus l/CLR(renal clearance) of azosemide yielded a straight line in six rabbits, indicating that the CLRof azosemide is urine flow dependent in rabb

ISSN:0142-2782    

DOI:10.1002/bdd.2510150405

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe pharmacokinetics of SDZ 64–412, an antiasthmatic agent, were investigated following intravenous, oral, and inhalation dosing in rats.14C‐SDZ 64–412 was administered intravenously (2.75 mg kg−1) and orally (5.5 mg kg−1, 110 mg kg−1), whereas non‐radiolabeled drug (5.04 mg kg−1) was administered using nose‐only inhalation chambers. Radioactivity and parent drug concentrations in blood, lung, and excreta were determined at designated times post‐dose. SDZ 64–412 was rapidly and extensively (∼80%) absorbed following both oral doses, although absorption appeared to be prolonged with increasing dose. The absorbed drug was shown to undergo extensive and saturable first‐pass metabolism. The bioavailability of the parent drug, calculated by dose‐normalized AUC and deconvolution methods, was only 10–15% from the low dose, but increased to ∼40% following the high dose. Following inhalation dosing, SDZ 64–412 concentrations in blood and lungs increased rapidly, and did not decline immediately after termination of dosing. The inhalation dose yielded a bioavailability of ∼40%, and AUC of the drug in lungs was approximately 25 times greater than in blood. In general, SDZ 64–412 was extensively distributed and rapidly eliminated from the systemic circulation. Biliary excretion was the predominant route of radioactivity excretion. The present findings suggest that inhalation administration provides a v

ISSN:0142-2782    

DOI:10.1002/bdd.2510150406

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe systemic availability of a solid dispersion (coevaporate) of clofazimine (CLF) in poly(vinyl methyl ether maleic anhydride) copolymer (PVM/MA) was tested in the pig. Single 100 mg oral doses of the coevaporate and the commercial product, Lamprene® (Ciba‐Geigy) were administered on separate occasions (separated by a two‐week washout period) to four pigs (two males, two females) in a random cross‐over study. Multiple plasma samples, obtained from an indwelling jugular‐vein cannula, following drug administration, were analyzed by an HPLC method for CLF. Pharmacokinetic analyses of the plasma CLF concentration—time data were performed. A pairedt‐test indicated significant differences (p<0.05) between the coevaporate and Lamprene® in theCpmax,tmax, and AUC. The calculated relative systemic bioavailability (Frel) of CLF from the coevaporate, relative to that from Lamprene®, was three. It is concluded that formulation of CLF, as a solid dispersion, may provide enhanced aqueous dissolution and systemic absorption and may also provide high therapeutic blood levels. These could lead to reduction in the current therapeutic doses and, consequently, minimization of drug‐rela

ISSN:0142-2782    

DOI:10.1002/bdd.2510150407

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510150408

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY

ISSN:0142-2782    

DOI:10.1002/bdd.2510150401

出版商:John Wiley&Sons, Ltd.    

年代:1994

数据来源: WILEY