TABLE 4

Comparison of lansoprazole, dexlansoprazole, pantoprazole, and rabeprazole as CYP2C19 inhibitors

PPISubstrateKi,ua% Inhibitionpredictedb% Inhibitionin vivo (90% CI)c
CmaxCmax,uCmax.portalCmax,portal,u
μM
LansoprazoleDiazepam1.2748801119 (<1, 33)
(S)-Mephenytoin0.686169021
CEC0.294349642
(S)-Mephenytoin (HLM)0.391239330
DexlansoprazoleDiazepam6.1381d10 (2, 19)
(S)-Mephenytoin3.0563
CEC1.1787
(S)-Mephenytoin (HLM)2.8593
PantoprazoleDiazepam3.694259425<1 (<1, 20)
(S)-Mephenytoin6.790159015
CEC2.196359635
(S)-Mephenytoin (HLM)>20<74<5<74<5
RabeprazoleDiazepam>20<2<1<4<1<1 (<1, 3)
(S)-Mephenytoin5.77<112<1
CEC2.118<1282
(S)-Mephenytoin (HLM)121<16<1
  • a Unless otherwise indicated, the Ki,u is the IC50 with rCYP2C19 (Table 2) divided by 2 (not corrected for fu,inc because binding to rCYP2C19 was negligible: fu,inc >0.97). For (S)-mephenytoin with HLM only, the Ki,u is the IC50 obtained with HLM, corrected for fu,inc and then divided by 2. No time-dependent effect was observed after preincubation of these PPIs with HLM, so only reversible inhibition was considered.

  • b Percentage of inhibitionpredicted was determined as described under Materials and Methods. Cmax (Cmax,u) values for each PPI were based on those reported for a specific diazepam drug interaction; 3.4 (0.11) μM after 60 mg of oral lansoprazole, 4.0 (0.08) μM after 90 mg of oral dexlansoprazole, 57 (1.1) μM after 240 mg of IV pantoprazole, and 0.45 (0.02) μM after 20 mg of oral rabeprazole (see Supplement Table S2). Cmax,portal values were 4.8 μM (lansoprazole), 57 μM (pantoprazole), and 0.8 μM (rabeprazole). Corresponding Cmax,portal,u values were 0.14 μM (lansoprazole), 1.1 μM (pantoprazole), and 0.03 μM (rabeprazole).

  • c Percentage of inhibitionin vivo was calculated based on the reported effect of each PPI on the AUC of diazepam (see Materials and Methods, eqs. 17 and 18).

  • d No clinical IV data available in the literature for dexlansoprazole, so it was not possible to estimate Cmax,portal.