Linked Life Data

9622082

Source:http://linkedlifedata.com/resource/pubmed/id/9622082

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1998-7-7
pubmed:abstractText
Carzelesin is a novel cyclopropylpyrroloindole prodrug analogue that has recently been tested in Phase I clinical trials. To increase our understanding in the pharmacology of this new class of cytotoxic drugs, we have compared the pharmacology of this drug in mice, rats, and humans. The mouse was the most tolerant [10% lethal dose (LD10), 500 microg/kg], the rat was intermediate (LD10, 40 microg/kg), and humans were the least tolerant species in this series (maximum tolerated dose, 300 microg/m2 corresponding to 7.5 microg/kg). In both mice and humans, bone marrow toxicity was the primary toxic side effect. Pharmacokinetic studies, using a validated high-performance liquid chromatographic procedure, revealed that differences in drug clearance and conversion to the active drug (U-76,074) could not explain the substantial interspecies differences. The area under the plasma concentration time curve (AUCs) of carzelesin in mice and rats at their LD10s were about 80- and 20-fold higher, respectively, than in humans receiving the maximum tolerated dose, whereas the respective AUCs of U-76,074 in mice and rats were 50- and 10-fold higher. By using a colony-forming assay with bone marrow stem cells from mice and humans, we observed only a 3-fold higher toxicity in the latter. Although some of this discrepancy may be explained by the fact that the in vitro and the in vivo assays probably reflect the toxicity on different populations of colony-forming units, the tolerance of the mouse bone marrow in vivo against the very high drug levels in plasma suggest the presence of a protective mechanism, which is less active in humans. An important consequence of the much higher susceptibility of the human bone marrow for carzelesin is that the target plasma levels in humans are much below active concentrations achieved in mice, and it is clear that this may compromise the successful use of this agent in the clinic. Ultimately, however, the efficacy of this drug will be established in Phase II clinical trials.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
58
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2410-6
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Comparative pharmacology of the novel cyclopropylpyrroloindole-prodrug carzelesin in mice, rats, and humans.
pubmed:affiliation
Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam. OTEL@nki.nl
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't