Leflunomide increased the renal exposure of acyclovir by inhibiting OAT1/3 and MRP2

Abstract

Rheumatoid arthritis patients can be prescribed a combination of immunosuppressive drug leflunomide (LEF) and the antiviral drug acyclovir to reduce the high risk of infection. Acyclovir is a substrate of organic anion transporter (OAT) 1/3 and multidrug resistance-associated protein (MRP) 2. Considering the extraordinarily long half-life of LEF’s active metabolite teriflunomide (TER) and the kidney injury risk of acyclovir, it is necessary to elucidate the potential impact of LEF on the disposition of acyclovir. Here we used a specific MRP inhibitor MK571 and probenecid (OAT1/3 and MRP2 inhibitor) to assess the effects of MRP2 and OAT1/3 on the pharmacokinetics and tissue distribution of acyclovir in rats. We showed that LEF and probenecid, but not MK571 significantly increased the plasma concentration of acyclovir. However, kidney and liver exposures of acyclovir were increased when coadministered with LEF, probenecid or MK571. The kidney/plasma ratio of acyclovir was increased to approximately 2-fold by LEF or probenecid, whereas it was increased to as much as 14.5-fold by MK571. Consistently, these drugs markedly decreased the urinary excretion of acyclovir. TER (0.5−100 μmol/L) dose-dependently increased the accumulation of acyclovir in MRP2-MDCK cells with an IC 50 value of 4.91 μmol/L. TER (5 μmol/L) significantly inhibited the uptake of acyclovir in hOAT1/3-HEK293 cells. These results suggest that LEF/TER increased the kidney accumulation of acyclovir by inhibiting the efflux transporter MRP2, which increased its kidney/plasma ratio and renal injury risk. However, the inhibitory effects of LEF/TER on OAT1/3 reduced the tubular cells’ uptake of acyclovir and increased the plasma concentration.

Teriflunomide‐associated urolithiasis: a new adverse reaction explained by its uricosuric effect

“…An explanation of the uricosuric effect of teriflunomide could be based on its ability to increase urate tubular secretion and/or to decrease urate tubular reabsorption, leading to supersaturation of UA levels and subsequent formation of monosodium urate crystals in the urinary tract. Nevertheless, based on its inhibitory effects on organic anion transporters 1 and 3 (OAT1/3) and its high affinity for the breast cancer resistance protein (BCRP) [5], teriflunomide is expected to inhibit UA tubular secretion, leading to increased uricemia. In this sense, teriflunomide exposure exhibited a strong positive correlation with serum UA levels in healthy individuals [6].…”

Simultaneous Determination of Amlodipine and Valsartan in Tablet By UV Spectrophotometry With Successive Ratio Method

“…Synergic effect has been observed with ketoconazole, though not clinically proved 13 . Increased half-life and decreased urinary excretion of acyclovir have been reported when administered along with probenecid 14 . Patients need to be cautious about taking acyclovir while receiving IV because of the synergistic effect.…”