Effect of Chronic Administration of Ritonavir on Function of Cytochrome P450 3A and P-Glycoprotein in Rats

Kageyama, Michiharu; Namiki, Hitomi; Fukushima, Harumi; Terasaka, Shuichi; Togawa, Tatsuya; Tanaka, Akina; Ito, Yoshiaki; Shibata, Nobuhito; Takada, Kanji

doi:10.1248/bpb.28.130

Cited by 46 publications

(43 citation statements)

References 33 publications

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“…Plasma was immediately separated by centrifugation at 7,500 rpm for 15 min from the blood samples and stored in frozen conditions at -20°C with appropriate labelling of subject code number, study date, and collection time prior to analysis. The concentration of ritonavir in rat plasma samples was measured by the reverse-phase high-performance liquid chromatography (HPLC) (Lledo et al 2007;Kageyama et al 2005).…”

Section: Lyophilization Cyclementioning

confidence: 99%

Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

2015

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The aim of the present study was to formulate and evaluate the ritonavir-loaded stealth liposomes by using 3 2 factorial design and intended to delivered by parenteral delivery. Liposomes were prepared by ethanol injection method using 3 2 factorial designs and characterized for various physicochemical parameters such as drug content, size, zeta potential, entrapment efficiency and in vitro drug release. The optimization process was carried out using desirability and overlay plots. The selected formulation was subjected to PEGylation using 10 % PEG-10000 solution. Stealth liposomes were characterized for the above-mentioned parameters along with surface morphology, Fourier transform infrared spectrophotometer, differential scanning calorimeter, stability and in vivo pharmacokinetic studies in rats. Stealth liposomes showed better result compared to conventional liposomes due to effect of PEG-10000. The in vivo studies revealed that stealth liposomes showed better residence time compared to conventional liposomes and pure drug solution. The conventional liposomes and pure drug showed dose-dependent pharmacokinetics, whereas stealth liposomes showed long circulation half-life compared to conventional liposomes and pure ritonavir solution. The results of statistical analysis showed significance difference as the p value is (\0.05) by one-way ANOVA. The result of the present study revealed that stealth liposomes are promising tool in antiretroviral therapy.

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Section: Lyophilization Cyclementioning

confidence: 99%

Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

2015

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“…10,11) According to the literature, all three drugs used in this study show affinity for the binding sites on the Pgp protein, with verapamil having the highest affinity. 2,30,31) However in the LPV/r combination the concentration of lopinavir is higher and lopinavir out-competes ritonavir for binding to the P-gp protein, as seen in Fig. 1C.…”

Section: Discussionmentioning

confidence: 93%

“…1,2) The PI's are substrates for CYP P450 oxidative metabolism, predominantly CYP3A4. 3) However, most of the PI's inhibit CYP3A4 specifically, 3) with ritonavir being one of the most potent.…”

mentioning

confidence: 99%

“…5) However, contradictory reports have found that plasma concentrations of ritonavir, or other co-administered drugs, are 'reduced' after chronic ritonavir treatment. 2,6,7) The multidrug efflux transporter, P-gp, is responsible for extracting substrate drugs from the site of absorption, and as such limits their intracellular drug accumulation and can thus contribute to treatment failure. 8) P-gp is an ATP-dependant membrane transporter with broad substrate specificity, capable of mediating efflux of a variety of structurally diverse drugs.…”

mentioning

confidence: 99%

“…23) Importantly, the induction of CYP3A in SpragueDawley rats following ritonavir treatment and the measurement of ritonavir activity in the blood-brain barrier and intestinal mucosa has been described. 24) Although studies in rats to investigate drug interactions between ritonavir and lopinavir have primarily focussed on treatments of shorter duration, 2) studies over a longer period of time are limited and require clarification, especially because of the obligatory role of long-term drug treatment in patients receiving these drugs. To our knowledge, the present study is the first to investigate the time-dependent effects of P-gp inhibition over 1, 7 and 21 d on the plasma levels of the ritonavir and lopinavir (LPV/r) combination, compared to that of ritonavir given alone.…”

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Evidence for Time-Dependent Interactions between Ritonavir and Lopinavir/Ritonavir Plasma Levels Following P-Glycoprotein Inhibition in Sprague-Dawley Rats

Plooy

Viljoen

Rheeders

2011

Biological & Pharmaceutical Bulletin

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Protease inhibitors (PI's), such as ritonavir and lopinavir, form an integral part of combination antiretroviral therapy. The metabolism of the PI's is complex and is influenced by both the cytochrome P450 (CYP P450) enzymes in the liver as well as the efflux transporter, P-glycoprotein (P-gp). 1)However, there is conflicting reports in the literature on the influence of these two systems on the plasma levels of lopinavir and ritonavir after acute and chronic treatment. 1,2)The PI's are substrates for CYP P450 oxidative metabolism, predominantly CYP3A4.3) However, most of the PI's inhibit CYP3A4 specifically, 3) with ritonavir being one of the most potent. Earlier studies have found that ritonavir markedly increases the plasma concentration and prolongs the elimination of many concomitant drugs. 4) Indeed, the combination of ritonavir and lopinavir (LPV/r) has been designed specifically on the ability of ritonavir to enhance the bioavailability of lopinavir. 4) Studies in rats have noted that the bioavailability of lopinavir can be lower by as much as 25% when administered alone as compared to its levels following the administration of LPV/r. Moreover, the combination is associated with a significant increase in maximum plasma concentration (C max ) and area under the curve (AUC) for both ritonavir and lopinavir. 5) However, contradictory reports have found that plasma concentrations of ritonavir, or other co-administered drugs, are 'reduced' after chronic ritonavir treatment. 2,6,7)The multidrug efflux transporter, P-gp, is responsible for extracting substrate drugs from the site of absorption, and as such limits their intracellular drug accumulation and can thus contribute to treatment failure. 8) P-gp is an ATP-dependant membrane transporter with broad substrate specificity, capable of mediating efflux of a variety of structurally diverse drugs.9) There is a strong suggestion that different binding sites exist on the P-gp transporter, 10,11) while there is also evidence of competitive and non-competitive inhibition of these sites. 11) P-gp is expressed in a multitude of organs such as the liver, intestinal epithelial cells, kidney and blood-brain barrier in both humans and rodents. [12][13][14] The expression of this glycoprotein and its action to limit drug absorption and penetration into a desired target organ has important therapeutic implications, including the potential for sub-therapeutic drug levels, viral resistance and contributing to treatment failure.15) Controversy relating to the effect of PI's on the P-gp transport system is widely recognised, including whether these drugs are responsible for P-gp induction, 16) whether ritonavir and lopinavir are P-gp inhibitors 17) or whether or not PI's affect P-gp expression. 18)The calcium channel blocker, verapamil, is often used as an inhibitor of P-gp to investigate interactions between antiretroviral (ARV) drugs.19) Despite the aforementioned controversy, the effect of P-gp on ARV therapy is nevertheless significant. A number of studies in the literatur...

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Assessment of CYP3A‐mediated drug–drug interaction potential for victim drugs using an in vivo rat model

Rioux

Bellavance

Bourg

et al. 2013

Biopharm & Drug Disp

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The present study aims to determine if an in vivo rat model of drug-drug interaction (DDI) could be useful to discriminate a sensitive (buspirone) from a 'non-sensitive' (verapamil) CYP3A substrate, using ketoconazole and ritonavir as perpetrator drugs. Prior to in vivo studies, ketoconazole and ritonavir were shown to inhibit midazolam hydroxylation with IC50 values of 350 ± 60 nm and 11 ± 3 nm, respectively, in rat liver microsomes (RLM). Buspirone and verapamil were also shown to be substrates of recombinant rat CYP3A1/3A2. In the rat model, the mean plasma AUC0-inf of buspirone (10 mg/kg, p.o.) was increased by 7.4-fold and 12.8-fold after co-administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. The mean plasma AUC0-inf of verapamil (10 mg/kg, p.o.) was increased by 3.0-fold and 4.8-fold after co-administration with ketoconazole and ritonavir (20 mg/kg, p.o.), respectively. Thus, the rat DDI model correctly identified buspirone as a sensitive CYP3A substrate (>5-fold AUC change) in contrast to verapamil. In addition, for both victim drugs, the extent of DDI when co-administered was greater with ritonavir compared with ketoconazole, in line with their in vitro CYP3A inhibition potency in RLM. In conclusion, our study extended the rat DDI model applicability to two additional victim/perpetrator pairs. In addition, we suggest that use of this model would increase our confidence in estimation of the DDI potential for victim drugs in early discovery.

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Effect of Chronic Administration of Ritonavir on Function of Cytochrome P450 3A and P-Glycoprotein in Rats

Cited by 46 publications

References 33 publications

Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

Evidence for Time-Dependent Interactions between Ritonavir and Lopinavir/Ritonavir Plasma Levels Following P-Glycoprotein Inhibition in Sprague-Dawley Rats

Assessment of CYP3A‐mediated drug–drug interaction potential for victim drugs using an in vivo rat model

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