Loganin Ameliorates Acute Kidney Injury and Restores Tofacitinib Metabolism in Rats: Implications for Renal Protection and Drug Interaction

Abstract

Tofacitinib, a Janus kinase (JAK) inhibitor used to treat rheumatoid arthritis, is metabolized through hepatic cytochrome P450 (CYP), specifically CYP3A1/2 and CYP2C11. Prolonged administration of rheumatoid arthritis medications is generally associated with an increased risk of renal toxicity. Loganin (LGN), an iridoid glycoside, has hepatorenal regenerative properties. This study investigates the potential of LGN to mitigate acute kidney injury (AKI) and its effects on the pharmacokinetics of tofacitinib in rats with cisplatin-induced AKI. Both intravenous and oral administration of tofacitinib to AKI rats significantly increased the area under the plasma concentration-time curve from time 0 to infinity (AUC) compared with control (CON) rats, an increase attributed to the decelerated non-renal clearance (CL_NR) and renal clearance (CL_R) of tofacitinib. Administration of LGN to AKI rats, however, protected kidneys from severe impairment, restoring the pharmacokinetic parameters (AUC, CL_NR, and CL_R) of tofacitinib to those observed in untreated CON rats, with partial recovery of kidney function, as evidenced by an increase in creatinine clearance (CL_CR). Possible interactions between drugs and natural components should be considered, especially when co-administering both a drug and a natural extract containing LGN or iridoid glycosides to patients with kidney injury.

Keywords: Acute kidney injury; CYP2C11; CYP3A1/2; Loganin; Pharmacokinetics; Tofacitinib.

Fig. 1

Chemical structures of (A) tofacitinib and (B) loganin.

Fig. 2

(A) Body weight, plasma chemistry data, creatinine clearance (CLCR), plasma protein binding of tofacitinib, and relative liver and kidney weights in the four groups of rats (control (CON), loganin (LGN), acute kidney injury (AKI) and acute kidney injury-loganin (AKI-LGN); n=3 each). Data are shown as means ± standard deviations. (B) Liver and kidney biopsy samples from rats in the four groups. Black arrows indicate immune cell infiltration and stars indicate tissue damage, including massive cell death. BUN, blood urea nitrogen; BW, body weight; GOT, glutamate oxaloacetate transaminase; GPT, glutamate pyruvate transaminase; SCR, serum creatinine concentration. *p<0.05, **p<0.01, ***p<0.001.

Fig. 3

Mean arterial plasma concentration-time profiles of tofacitinib after (A) 1-min intravenous infusion (10 mg/kg) into control (CON, n=6), loganin (LGN, n=6), acute kidney injury (AKI, n=7) and acute kidney injury-loganin (AKI-LGN, n=6) rats, and (B) oral administration (20 mg/kg) to CON (n=5), LGN (n=5), AKI (n=6) and AKI-LGN (n=7) rats. Bar represent standard deviations.

Fig. 4

Mean Vmax, Km and CLint values for tofacitinib metabolism in (A) hepatic and (B) intestinal microsomes from control (CON), loganin (LGN), acute kidney injury (AKI) and acute kidney injury-loganin (AKI-LGN) rats (n=3 per group). Data are shown as means ± standard deviations of three independent experiments. Vmax, maximum velocity; Km, apparent Michaelis–Menten constant; CLint, intrinsic clearance. *p<0.05; **p<0.01; ***p<0.001.

Fig. 5

Immunoblot analyses of cytochrome P450 (CYP) isozymes in (A) hepatic and (B) intestinal microsomes from control (CON), loganin (LGN), acute kidney injury (AKI) and acute kidney injury-loganin (AKI-LGN) rats. β-Actin was used as a loading control. Results are representative of three independent experiments. Band density was measured using ImageJ 1.45s software (NIH).