Impact of Physicochemical Properties on Dose and Hepatotoxicity of Oral Drugs

Abstract

A database containing maximum daily doses of 1841 marketed oral drugs was used to examine the influence of physicochemical properties on dose and hepatotoxicity (drug induced liver injury, DILI). Drugs in the highest ∼20% dose range had significantly reduced mean lipophilicity and molecular weight, increased fractional surface area, increased % of acids, and decreased % of bases versus drugs in the lower ∼60% dose range. Drugs in the ∼20-40% dose range had intermediate mean properties, similar to the mean values for the full drug set. Drugs that are both large and highly lipophilic almost invariably do not have doses in the upper ∼20% range. The results show that oral druglike physicochemical properties are different according to these dose ranges, and this is consistent with maintenance of acceptable safety profiles as efficacious exposure increases. Verified DILI annotations from a compilation of >1000 approved drugs (Chen, M.; et al. Drug Discov. Today, 2016, 21, 648 ) were used. The drugs classified as "No DILI" ( n = 163) had significantly lower dose and lipophilicity, and higher Fsp3 (fraction of carbon atoms that are sp hybridized) versus the "Most DILI" ( n = 163) drugs. The percentages of acids were reduced and bases increased in the "No DILI" versus the "Most DILI" groups. Drugs classified as "Less DILI" or "Ambiguous DILI" had intermediate mean values of dose, lipophilicity, Fsp3, and % acids and bases. The impact of lipophilicity and Fsp3 on DILI increases in the upper 20% versus the lower 80% dose range, and a simple decision tree model predicted "No DILI" versus "Most DILI" outcomes with 82% accuracy. The model correctly classified 19 of 22 drugs (86%) that failed in development due to human hepatotoxicity. Because many oral drugs lacking DILI annotations are predicted to be "Most DILI", the model is best used preclinically in conjunction with experimental DILI mitigation.

Computational Assessment of the Pharmacological Profiles of Degradation Products of Chitosan

“…The hepatotoxicity of investigated COs also seems to depend on the molecular weight, the oligomers having the molecular weights between 500 and 1500 Da reflecting a weak potential of hepatotoxicity. This result is also in good correlation with published data revealing that lipophilicity and molecular weight are the most important physicochemical properties that influence the drug induced liver injury (Leeson, 2018). Furthermore, there is a slight dependence of hepatotoxicity of COs on the deacetylation degree and pattern.…”

Computational Models Using Multiple Machine Learning Algorithms for Predicting Drug Hepatotoxicity with the DILIrank Dataset

“…Nordihydroisomorphine, the first compound, for instance, is a metabolite of hydromorphone that has been isolated from urine [58]; it seems likely, therefore, that it is hydrophilic and needs little liver metabolizing. It is known that drugs with higher lipophilicity tend to be hepatotoxic, whereas those with low lipophilicity tend to be non-hepatotoxic [59]. Trihexyphenidyl or adrenor (norepinephrine) were already in the dataset as non-hepatotoxic.…”

Physicochemical properties and Mycobacterium tuberculosis transporters: keys to efficacious antitubercular drugs?

“…It is thus perhaps not unexpected that for effective TB treatment high drug doses are often required, which can compromise narrow safety windows and increases the risk of adverse side effects. 29,49 The use of bedaquiline, which is only approved to treat multi-drug resistant TB, is a case in point where the advantages of successful TB treatment outweighs the 'black box' warning of cardiovascular and hepatic toxicity risks and usage limited to drug resistant cases; it is notable that all three of the most recently licenced TB medicines are in higher risk space as defined by PFI estimates, unlike more established drugs. The analysis of this set using the GSK log D 7.4 /CMR model reveals that TB drugs are localised at the fringes when compared to the distribution of marketed oral drugs ( Fig.…”