n-Octanol/Water partition
coefficient (log P)
The 1-octanol/water partition coefficient (log P)
for 1-octanol/distilled water was –1.32.
For pH 1.2, the log P was –0.60, for pH 6, the log P was 0.91 and for pH
7.4, the log P was 1.54.
Summary
the log P values are all less than 2, therefore
bupropion hydrochloride is not expected to significantly bioconcentrate or to
sorb onto organic particles. The
terrestrial compartment should not be directly affected.
7.d Bioavailability and Metabolites
The absolute bioavailability of bupropion
hydrochloride in man is not known, since the drug has never been administered
intravenously. In animals, the
bioavailability was low (5-10%), due to extensive first-pass metabolism. There are three basic metabolites found in
plasma: 306U73 (0.568% as active as bupropion in animal models), 17U67 and
494U73 (an erythro-threo pair of isomers, 0.208% as active) with 306U73 being
the major metabolite and 494U73 present at about four times the concentration
of 17U67. The major urinary metabolite
is m-chlorohippuric acid, the glycine conjugate of m-chlorobenzoic
acid, which is also present in urine.
When 14C-bupropion was administered to seven healthy
volunteers, recovery of the radioactive dose was nearly complete with 86% recovered
in urine and 10% recovered in feces.
The radioactivity in the urine consisted of unchanged bupropion
(<1%), 306U73 (5%), 494U73 (6%), 17U67 (2%), m-chlorohippuric acid
(24%), m-chlorobenzoic acid (<1%), glucuronides of 17U67 and/or
494U73 (10%), and 3 unidentified polar metabolites (8, 11, and 25%,
respectively). See the Table of
Nomenclature in the CONFIDENTIAL Appendix A (NOT PROVIDED THROUGH FOI
ACT) for structures of these metabolites.
8.
ENVIRONMENTAL EFFECTS OFF RELEASED SUBSTANCE
Based on the outcome of Tier 0 tests, bupropion
hydrochloride is most likely to affect the aquatic compartment. In order to determine the environmental
effects of bupropion hydrochloride on organisms in the aquatic environment, the
microbial growth inhibition potential was measured.
Microbial Growth Inhibition
Non-radiolabeled bupropion hydrochloride was
evaluated for potential inhibitory effects on the growth of five pure cultures
of bacteria, fungi, and blue-green algae (see Attachment V). No inhibition was observed for two of the
test organisms (Azotobacter chroococcum and Pseudomonas fluorescens). Three test organisms (Chaetomium globosum,
Aspergillus flavus, and Nostoc sp.) indicated a minimum
inhibitory concentration (MIC) of 100 mg/L.
the MIC (Minimum Inhibitory Concentration) is defined as the lowest
concentration that inhibits microbial growth.
Therefore the LC50 is 100 ppm.
GCPV/93/0011/03 13
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