Effect of compromised liver function and acute kidney injury on the pharmacokinetics of thymoquinone in a rat model

Abstract

1. The current research explored the effect of hepatic and renal dysfunctions on the pharmacokinetics of thymoquinone (TQ) in a rat model.

2. An acute kidney injury was induced using gentamicin and a liver damage was elicited using a single dose of d-galactosamine. For the pharmacokinetic studies, TQ was administered as IV injection or and PO route to rats.

3. The concentrations of TQ and pharmacokinetic parameters were calculated using a non-compartmental analysis. The systemic clearance (Cl) of TQ after IV dosing was slightly reduced in the liver dysfunction group compared to healthy controls (p = 0.0013). Similarly, the estimated volume of distribution at steady state (Vss) was marginally decreased (p = 0.001). However, in rats with acute kidney injury exhibited a larger Vss as opposed to normal renal function (511.28 ± 21.03 ml/kg vs. 442.25 ± 31.43 ml/kg; p = 0.0001). Whereas oral Cl and terminal volume of distribution (Vz) of TQ were reduced by ∼50% in the liver dysfunction group (p = 0.0001). These changes were associated with more systemic exposure as measured by AUC_0–∞ in rats with compromised liver functions. The estimated plasma protein binding TQ was 99.84 ± 0.03% in healthy controls, 97.05 ± 0.57% with kidney injury rats, and 95.75 ± 0.64% in liver dysfunction

4. The findings of the present study suggest that liver dysfunction could potentially modify the disposition of TQ administered orally, and therefore, a smaller maintenance dose is probably required to avoid accumulation.

Keywords:

• Thymoquinone
• liver dysfunction
• kidney injury
• pharmacokinetics
• animal model
• plasma protein binding

Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding this work through research group no. RG-1441-337.

Ethical approval

All procedures performed were in accordance with international and national, and were approved by the College of Pharmacy Ethical Committee, King Saud University (KSU-SE-19-17).

Author contribution

KMA and AA, study design; FAA, MAA, BLJ and MR, conducted experiments; KMA, AA and SA, data analyses; MKA and AA, writing of the manuscript. All the authors reviewed the manuscript.

Disclosure statement

The authors declare no conflict of interests.

Additional information

Funding

This work was supported by Deanship of Scientific Research, King Saud University [RG-1441-337].