Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses*

Olbricht, Christoph J.; Wanner, Christoph; Eisenhauer, T.; Kliem, Volker; Doll, Rainer; Boddaert, Michel; O'Grady, P.; Krekler, Michael; Mangold, Bernhard; Christians, Uwe

doi:10.1016/s0009-9236(97)90034-5

Cited by 145 publications

(87 citation statements)

References 23 publications

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“…Because pravastatin is not metabolized, this increase is likely to be attributed to the inhibition of hepatic uptake transporters. These results confirmed results of an earlier study performed in patients who underwent kidney transplantation and are receiving pravastatin or lovastatin together with CsA [Table 3 (Olbricht et al, 1997)]. It is noteworthy that, in this study, it was demonstrated that pravastatin coadministered with CsA did not accumulate over the study period, even if the AUC was 5-fold higher than values reported in the absence of CsA (AUC for single dose at day one: 249 mg Â h/ml, AUC for multiple doses after 28 days: 241 mg Â h/ml), whereas lovastatin accumulated over time in CsA-treated patients (AUC for single dose at day one: 243 mg Â h/ml, AUC for multiple doses after 28 days: 459 mg Â h/ml).…”

Section: Drug-drug Interactionssupporting

confidence: 90%

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

2013

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Section: Drug-drug Interactionssupporting

confidence: 90%

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

2013

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“…Cyclosporine, for instance, inhibited OATP1B1-and OATP1B3-mediated drug uptake in vitro (Treiber et al, 2007). Thus, it has been observed in humans that coadministration of the OATP1B1 and OATP1B3 substrate pravastatin with cyclosporine increased the plasma concentrations of pravastatin (Regazzi et al, 1993;Olbricht et al, 1997;Park et al, 2002;Hedman et al, 2004). Because pravastatin is not metabolized to a significant extent (Jacobsen et al, 1999), inhibition of OATP1B1-and OATP1B3-mediated pravastatin uptake may be one relevant molecular mechanism behind this observed drug-drug interaction.…”

Section: Discussionmentioning

confidence: 99%

Influence of Non-Steroidal Anti-Inflammatory Drugs on Organic Anion Transporting Polypeptide (OATP) 1B1- and OATP1B3-Mediated Drug Transport

Kindla

Müller²,

Mieth³

et al. 2011

Drug Metab Dispos

101

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ABSTRACT:The transporter-mediated uptake of drugs from blood into hepatocytes is a prerequisite for intrahepatic drug action or intracellular drug metabolism before excretion. Therefore, uptake transporters, e.g., members of the organic anion transporting polypeptide (OATP) family are important determinants of drug pharmacokinetics. Highly and almost exclusively expressed in hepatocytes are the OATP family members OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3). Drug substrates of OATP1B1 and OATP1B3 include antibiotics and HMG-CoA reductase inhibitors (statins). It has been demonstrated that administration of two or more drugs that are substrates for these hepatic uptake transporters may lead to transporter-mediated drug-drug interactions, resulting in altered transport kinetics for drug substrates. In this study we investigated whether non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol interact with OATP1B1 and OATP1B3 using the standard substrate BSP and the drug substrate pravastatin. Using human embryonic kidney cells stably expressing OATP1B1 or OATP1B3, we demonstrated that bromosulfophthalein uptake was inhibited by diclofenac, ibuprofen. and lumiracoxib. Of interest, pravastatin uptake was stimulated by these NSAIDs, and for ibuprofen we determined activation constants (EC 50 values) of 64.0 and 93.1 M for OATP1B1-and OATP1B3-mediated uptake, respectively. Furthermore, we investigated whether NSAIDs were also substrates for OATP1B1 and OATP1B3 and demonstrated that only diclofenac was significantly transported by OATP1B3, whereas all other NSAIDs investigated were not substrates for these uptake transporters. These results demonstrated that drugs may interact with transport proteins by allosteric mechanisms without being substrates and, therefore, not only uptake inhibition but also allosteric-induced modulation of transport function may be an important mechanism in transporter-mediated drug-drug interactions.

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“…This is because lovastatin is metabolized by CYP3A4, whereas the major pravastatin metabolites are generated by non-CYPdependent processes. 38,39) The AUC of bosentan nearly doubled after seven days of co-administration with cyclosporine, but the AUC values of cyclosporine were the same for doses with and without bosentan. 40) Bosentan is metabolized by CYP3A4 and CYP2C9, but it also induces these CYPs.…”

Section: Ešect Of Cyclosporine and Tacrolimus On Cyp3a4-mediated Nimentioning

confidence: 98%

Effect of Cyclosporine and Tacrolimus on Cytochrome P450 Activities in Human Liver Microsomes

et al. 2007

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The eŠects of cyclosporine and tacrolimus on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresoruˆn O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4′ -hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6b-hydroxylation activities in human liver microsomes were compared. Cyclosporine and tacrolimus, at concentrations of 0.2 or 2 mM, neither inhibited nor stimulated any of the metabolic activities except for those of CYP3A4. On the other hand, cyclosporine and tacrolimus competitively inhibited CYP3A4-mediated nifedipine oxidation activity, with inhibition constants (K i ) of 1.42 and 0.36 mM, respectively. In addition, 20 mM cyclosporine inhibited CYP2C19 and CYP2D6 activities by 29％ and 30％, respectively. These results suggest that tacrolimus would not cause clinically signiˆcant interactions with other drugs, which are metabolized by CYPs, via the inhibition of hepatic metabolism and that the reason why cyclosporine, but not tacrolimus, has a pharmacokinetic inhibitory eŠect might be that the dosage and/or the unbound concentrations around its metabolic enzymes are higher than those of tacrolimus, rather than the diŠerences in the inhibition potential. Obvious substrate-dependent eŠects on CYP3A4-inhibition potential were not observed.

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Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses*

Abstract: In contrast to lovastatin, pravastatin did not accumulate over the study period, which is probably one of the reasons rhabdomyolysis has been reported in lovastatin-treated but not pravastatin-treated transplant patients receiving cyclosporine immunosuppression.

Cited by 145 publications

References 23 publications

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

Influence of Non-Steroidal Anti-Inflammatory Drugs on Organic Anion Transporting Polypeptide (OATP) 1B1- and OATP1B3-Mediated Drug Transport

Effect of Cyclosporine and Tacrolimus on Cytochrome P450 Activities in Human Liver Microsomes

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