Naphthalene-2,6-dicarboxylic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Materials and methods

Objective of study:

absorption

bioaccessibility (or bioavailability)

distribution

enzyme inhibition / induction

excretion

metabolism

other: Blood Brain Barrier, P-gp Specificity, Cytochrome P450 inhibition, P450 regioselectivity, Human Intestinal Absorption, Aqueous solubility, Plasma Protein Binding

Test guideline

Qualifier:

according to guideline

Guideline:

other: ADME prediction software packages, ACD/ADME (v 5.0) and DS/ADMET (v 2.5.5)

Results and discussion

Main ADME results

Main ADME results 1

Type:

metabolism

Results:

Naphthalene-2,6-dicarboxy-lic acid would not be an inhibitor of CYP450 and could be metabolized in vivo

Main ADME results 2

Type:

other: P-gp Specificity

Results:

Naphthalene-2,6-dicarboxy-lic acid might not be an inhibitor or substrate of P-gp

Main ADME results 3

Type:

other: Plasma Protein Binding

Results:

Naphthalene-2,6-dicarboxy-lic acid could bind with plasma proteins with a binding ratio of 94%

Main ADME results 4

Type:

other: Bioavailability

Results:

Naphthalene-2,6-dicarboxy-lic acid may have a high oral bioavailability with a F% > 70%

Main ADME results 5

Type:

other: Blood Brain Barrier

Results:

Naphthalene-2,6-dicarboxy-lic acid may not easily pass the BBB

Main ADME results 6

Type:

absorption

Results:

Naphthalene-2,6-dicarboxy-lic acid could be absorbed in small intestine

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Plasma Protein Binding Ratio (PPB%): 94%, RI=0.53.
LogKaHSA: 4.01. The parameter represents the binding constant between compound and human serum albumin (HSA). RI=0.7.
Normally, the binding rate more than 95% means a high binding rate on plasma protein, 90% to 95% for a moderate binding rate, and less than 90% for a low binding rate8.ACD/ADME-Distribution calculations indicated that Naphthalene-2,6-dicarboxylic acid could bind with plasma protein in vivo with a moderate binding ratio of 94%. Furthermore, the compound could bind mainly with albumin but not with lipoprotein since it’s an organic acid.

Details on excretion:

As described above, the compound Naphthalene-2,6-dicarboxylic acid could be transfered into metabolites. These metabolites with an increased water-solubilitycould be excreted by the urine. Furthermore, the urine excretion rates of terephthalic acid, the similar compound of Naphthalene-2,6-dicarboxylic acid, in rats was detected to be about 50%, 52% and 53% in 0-24 hr, 0-48 hr and 0-72 hr, respectively, after single oral administration in dose of 100 mg/kg. Therefore, Naphthalene-2,6-dicarboxylic acid could also be directly excreted by urine,sincethis organic acid can be dissociated into water-soluble naphthalene-2,6-dicarboxylate anion under the water environment of circulatory system.

Applicant's summary and conclusion

Conclusions:

In summary, ACD/ADME and DS/ADMET, respectively, were applied to estimate PK data ofnaphthalene-2,6-dicarboxylic acid. Based on the calculation data from these two different ADME prediction packages in combination with reported PK data of similar compounds, benzoic acid and terephthalic acid, we predicted the TK properties of Naphthalene-2,6-dicarboxylic acid. As predicted,the compound could be absorbed in small intestine, and mayhave a high oral bioavailability of F% more than 70%. In addition, the compound could not pass the BBB easily to have a distribution in brain. Furthermore, it was predicted that it would bind on blood plasma protein with a high binding ratio less than 95%. As predicted, Naphthalene-2,6-dicarboxylic acid might not be an inhibitor or substrate of P-gp. Moreover, this compound would not be an inhibitor of CYP450, and it could be transferred into hydroxylated metabolites by Phase I metabolism or 6-((carboxymethyl)carbamoyl)-2-naphthoic acid through carboxylamidation reaction with glycine, and these metabolites with increased water-solubility would be excreted by the urine.In addition, Naphthalene-2,6-dicarboxylic acidcould also be directly excreted by urine since the organic acid may be dissociated into Naphthalene-2,6-dicarboxylate anion in circulation system in vivo.