Effect of lipophilicity on drug distribution and elimination: Influence of obesity

Abstract

For a given passively-distributed lipophilic drug, the extent of in vivo distribution (pharmacokinetic volume of distribution, V d ) in obese individuals increases in relation to the degree of obesity. The present study had the objective of evaluating drug distribution in relation to in vitro lipophilicity, and the relative increase in V d associated with obesity across a series of drugs. Methods: Cohorts of normal-weight control and obese subjects received single doses of drugs ranging from hydrophilic (acetaminophen, salicylate) to lipophilic (imipramine, verapamil). Lipid solubility was measured by the log-transformed values of the high-pressure liquid chromatographic (HPLC) retention index (Log 10 (HPLC)), and the octanol-water partition coefficient (LogP).Results: Among normal-weight controls, V d normalized for protein binding was highly correlated with Log 10 (HPLC) (R 2 = .65) and with LogP (R 2 = .78). V d of all drugs was increased in the obese cohort, but the relative increase (compared to controls) for individual drugs was disproportionately greater as lipid solubility increased. Since clearance was unrelated to lipophilicity, the increased V d produced a parallel disproportionate increase in elimination half-life in the obese cohort that was associated with Log 10 (HPLC) (R 2 = .62). Conclusion:Lipophilicity is a principal correlate of in vivo V d , as well as the increased V d of drugs in obese patients. The consequent prolongation of half-life in obesity has clinical safety implications in terms of delayed drug accumulation and washout during and after chronic dosage. The magnitude and importance of this effect for a given drug depends on the degree of obesity, as well as the lipid-solubility of the specific drug.

Impact of Obesity on Brexpiprazole Pharmacokinetics: Proposal for Improved Initiation of Treatment

“…Relative to normal-weight patients of the same metabolizer status, all differences in t 1/2 and C max were significant (P < .005), while differences in AUC from time 0 extrapolated to infinity were not (Table 2). Consistent with previous research, [9][10][11][12][13][14][15] the clearance following a single 2 mg dose did not vary between normal-weight and obese cohorts, but V d showed nearly a 3-fold increase in obesity, presumably due to extensive distribution into adipose tissue (Table 2). Of note, the V d in normal-weight subjects following the 2 mg single-dose simulations are in agreement with the reported 1.56 L/kg V d following intravenous administration when considering brexpiprazole's high bioavailability of 95% and an average weight of 64.2 kg.…”

“…[1][2][3] The model-predicted increase in V d observed in obese individuals is more than would be expected on the basis of weight alone, which is consistent with previous findings for lipophilic drugs with high V d . 9 Label-Guided Titration. Following the label dosing protocol, normal-weight CYP2D6 EMs reached median C trough above EC50, EC80, and EC90 on days 3, 9, and 16, respectively.…”

“…8 Recent research has suggested that drugs displaying a high V d and lipophilicity may exhibit significantly different pharmacokinetics (PK) between normal-weight patients and obese patients. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] While these studies have not shown consistent changes in clearance attributable to obesity as such, the increased distribution into adipose tissue of obese subjects, as demonstrated by a marked increase in V d , results in a prolonged elimination half-life (t 1/2 ). The clinical effects of halflife prolongation include delayed attainment of steadystate concentrations after initiation of treatment as well as delayed drug washout after discontinuation.…”

Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling

“…The three drugs presented herein do not represent the full spectrum of drugs dosed in children with obesity. For the many drugs that are more lipid soluble, the degree of obesity is likely to have a far greater impact on the volume of distribution as previously demonstrated in adults [45][46][47]. The underlying PBPK models used to apply the virtual population were developed using sparse data in children without obesity, and it is difficult to attribute any bias in pediatric obese predictions to the underlying PBPK model or the novel virtual population.…”

Comprehensive strategies of machine-learning-based quantitative structure-activity relationship models

“…Therefore, to achieve the desired effect for a drug in an actual environment, the hydrophilicity and lipophilicity of the drug need to be considered ( Ditzinger et al, 2019 ). The main environmental factors of a solvent can be found in the study by Bruno et al., 2021 .…”