Drug metabolism and disposition : the biological fate of chemicals
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Drug Metab. Dispos. · Sep 1993
Differences in the stereoselective pharmacokinetics of pazinaclone (DN-2327), a new anxiolytic, and its active metabolite after intravenous and oral single doses to dogs.
The stereoselective pharmacokinetics of the new nonbenzodiazepine anxiolytic compound pazinaclone (DN-2327) were studied in four beagle dogs after oral (2.5 mg/kg) and intravenous (0.5 mg/kg) administration of racemate in a two-way, crossover study design. Racemic pazinaclone was highly cleared after intravenous administration at 2.09 +/- 0.78 l hr-1 kg-1. The total clearance and volumes of distribution (Vc, V beta, and Vss) of (S)-pazinaclone were significantly lower than those of the antipode. ⋯ Simultaneous model-dependent analysis of the intravenous plasma profiles for parent drug and metabolite suggested stereoselectivity of the active metabolite MII with shorter formation half-life for (S)-MII. However, in vitro metabolism by liver slices and our in vivo data indicated exclusive elimination of (S)- and (R)-pazinaclone through complete conversion to the MII metabolite (fm = 1). Thus, the clearances of (S)- and (R)-MII were calculated to be 0.89 and 7.89 l hr-1 kg-1, respectively, indicating pronounced stereoselectivity in the metabolite clearance.(ABSTRACT TRUNCATED AT 250 WORDS)
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Drug Metab. Dispos. · Sep 1992
Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer.
Topotecan, a semisynthetic water-soluble analog of camptothecin, is the first topoisomerase I-directed drug to enter clinical trial in the United States in over 20 yr. In this study, 30-min infusions of topotecan were administered daily for 5 days every 3 weeks at doses ranging from 0.5 to 2.5 mg/m2. Topotecan is reversibly hydrolyzed in a pH-dependent reaction in aqueous solutions to the ring-open hydroxy acid. ⋯ The relationship between topotecan dose and myelotoxicity is well fit by a sigmoidal Emax model, as is the relationship between total topotecan area under the concentration-time curve and myelotoxicity. The disposition of topotecan was also studied in mice. The clearance rate for total topotecan in mice was 330 ml/min/m2 after administration of topotecan lactone.(ABSTRACT TRUNCATED AT 250 WORDS)
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Drug Metab. Dispos. · Jan 1991
Chronic stress impairs oxidative metabolism and hepatic excretion of model xenobiotic substrates in the rat.
Traumatic injury to both hard and soft tissue has been associated with a decrease in the rate of hepatic drug metabolism. The mechanism(s) underlying this phenomenon have yet to be determined, but may involve substances released from damaged tissues or activation of the adrenocortical axis secondary to stress. ⋯ In addition, the stressed animals evidenced a decreased rate of uptake of indocyanine green by the liver, an apparent decrease in the storage of the dye within the liver, and a decreased hepatic clearance of indocyanine green (presumably due to a decrease in the KM for biliary transport). These observations suggest that atraumatic stress affects several processes involved in the hepatobiliary disposition of xenobiotics.
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Drug Metab. Dispos. · Jan 1991
Dose-dependent stereopharmacokinetics of 5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sulfonamide-7,7 -dioxide , a potent carbonic anhydrase inhibitor, in rats.
[5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sul fonamide-7,7- dioxide] (MK-927), a potent carbonic anhydrase inhibitor capable of reducing intraocular pressure after topical application, is currently under investigation for the treatment of glaucoma. The purpose of this study was to characterize the pharmacokinetics of the enantiomers of MK-927 with particular emphasis on the effect of dose on the elimination kinetics. Because the drug resided primarily in erythrocytes, the kinetic analysis was generally performed based on the drug concentration of whole blood. ⋯ Clearly, the magnitude of stereoselectivity in the elimination kinetics of MK-927 enantiomers (40-fold) cannot be explained solely by stereoselective binding. Thus, other factors may also contribute to the overall stereoselectivity in the elimination kinetics of MK-927. The dose-dependent kinetics of the enantiomers was probably due to the saturable binding to carbonic anhydrase.
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Drug Metab. Dispos. · Nov 1990
Comparative StudySpecies comparison of pharmacokinetics and metabolism of diltiazem in humans, dogs, rabbits, and rats.
Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and related heart diseases. It is extensively metabolized into a host of metabolites, some of which have potent pharmacological activities. In this study, the pharmacokinetics and metabolism of DTZ was investigated in humans, dogs, rabbits, and rats after each species (n = 4 or 5) was given a single oral dose of DTZ. ⋯ The most abundant metabolites in urine appeared to be MA and deacetyl N,O-didesmethyl diltiazem, although there were considerable inter- and intra-species variations. Two additional metabolites were detected in the urine of the humans, dogs, and rabbits, but not in the rats. They were tentatively identified as O-desmethyl diltiazem and N-O-didesmethyl diltiazem, using electron impact and ammonia chemical ionization mass spectrometry.(ABSTRACT TRUNCATED AT 250 WORDS)