CPY3A4-Mediated Lopinavir Bioactivation and Its Inhibition by Ritonavir

Li, Feng; Lu, Jie; Ma, Xiaochao

doi:10.1124/dmd.111.041400

Cited by 30 publications

(25 citation statements)

References 31 publications

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“…In vitro studies were performed on rat everted gut sacs to determine the role of P-gp in the intestinal transport of felodipine. Everted sacs were incubated with felodipine alone and in combination with 10, 50 and 100 mg/mL of naringenin and ritonavir, standard P-gp and CYP3A4 inhibitor [24][25][26] . The transport of felodipine was increased in presence of naringenin and ritonavir ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…Effects of naringenin on felodipine transport across gut sac Everted sacs were filled with modified Krebs-Ringer bicarbonate (KRB) buffer (NaCl 6.9 g, KCl 0.35 g, MgSO 4 .7H 2 O 0.29 g, KH 2 PO 4 0.16 g, NaHCO 3 2.1 g, CaCl 2 0.28 g and 0.2% glucose, pH 7.3) containing felodipine 50 mg/mL in the presence or absence of ritonavir 50 mg/mL, standard Cytochrome P450 (CYP)3A4 and P-gp inhibitor [24][25][26] and naringenin 50, 100 and 200 mg/mL. Each sac was placed in individual 50 mL Erlenmeyer flasks contain 30 mL of oxygenated (O 2 /CO 2 ; 95:5) KRB and incubated at 37 C for 60 min in a shaker bath.…”

Section: Preparation Of Gut Sacmentioning

confidence: 99%

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Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacsin vitro

Sandeep¹,

Sridhar²,

Puneeth³

et al. 2013

Drug Development and Industrial Pharmacy

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The aim of this study was to investigate the effect of naringenin on the pharmacokinetics (PK) of felodipine in rats and membrane permeability across rat everted gut sacs in vitro. Rats were simultaneously co-administered with felodipine 10 mg/kg, p.o. and naringenin (25, 50 and 100 mg/kg, p.o.) for 15 consecutive days. Rats of the control groups received the corresponding volume of vehicle. Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS). The PK parameters were calculated using Thermo kinetica. The co-administration of naringenin significantly elevated the Cmax and increased the AUCtotal of felodipine in dose-dependent manner. The Cmax of felodipine was increased from 173.25 ± 14.65 to 275.61 ± 44.62 and 223.26 ± 26.35 to 561.32 ± 62.53 ng/mL in SDS and MDS, respectively, at the dose of naringenin 100 mg/kg. The AUCtotal of felodipine was significantly (p < 0.001) increased from 2050.48 ± 60.57 to 3650.22 ± 78.61 and 3276.51 ± 325.61 to 7265.25 ± 536.11 (ng/mL/h) in SDS and MDS, respectively. The permeability of felodipine was increased in presence of naringenin and ritonavir (standard P-glycoprotein (P-gp) and Cytochrome P450 (CYP)3A4 inhibitor). Felodipine is a substrate of CYP3A4, and naringenin was reported to be a modulator of P-gp and CYP3A4. These results suggest that naringenin significantly increased the Cmax and AUC of felodipine is due to P-gp and CYP3A4 inhibition.

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Section: Discussionmentioning

confidence: 99%

Section: Preparation Of Gut Sacmentioning

confidence: 99%

Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacsin vitro

Sandeep¹,

Sridhar²,

Puneeth³

et al. 2013

Drug Development and Industrial Pharmacy

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“…13) The INH bioactivation pathway was evaluated in liver microsomes of WT and Cyp3a -null mice. CYP3A-mediated bioactivation of LPV, 14) an HIV protease inhibitor, was used as a positive control. Compared to WT mice, bioactivation of LPV was significantly decreased in liver microsomes of Cyp3a- null mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Role of CYP3A in Isoniazid Metabolism In Vivo

Liu

et al. 2014

Drug Metabolism and Pharmacokinetics

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Summary Isoniazid (INH), a first-line drug for tuberculosis control, frequently causes liver injury. Multiple previous reports suggest that CYP3A is involved in INH metabolism, bioactivation and hepatotoxicity, although direct evidence is unavailable. In the current study, wild-type and Cyp3a-null mice were used to determine the potential role of Cyp3a in INH metabolism in vivo. Compared to wild-type mice, there were no significant differences in the pharmacokinetic profiles of INH and acetyl-isoniazid in Cyp3a-null mice after an oral administration of 50 mg/kg INH. With the same treatment, distribution of INH and its major metabolites was similar in the liver of wild-type and Cyp3a-null mice. A reactive metabolite of INH was trapped by N-α-acetyl-L-lysine in mouse liver microsomes, but Cyp3a does not contribute to this bioactivation pathway. In addition, no liver injury was observed in wild-type and Cyp3a-null mice treated with 60 or 120 mg/kg INH. In summary, Cyp3a has no effect on systemic pharmacokinetics of INH in mice. Further studies are needed to determine whether and how exactly CYP3A is involved in INH bioactivation and hepatotoxicity.

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“…The development of computational approaches to estimate pharmacokinetic and toxicity properties facilitates the progression of novel drug candidates 33. The prediction of metabolism or inhibition by the CYP3A4 indicates the need to perform further studies of interaction with drugs that inhibit the enzymes such as ritonavir and lopinavir 34. These compounds are predicted neither to be mutagenic nor to inhibit hERG I; however, interaction with hERG2 is predicted.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of <em>Trypanosoma cruzi</em> infection

Silva¹,

Batista²,

Araújo³

et al. 2017

DDDT

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Arylimidamides (AIAs), previously termed as reversed amidines, present a broad spectrum of activity against intracellular microorganisms. In the present study, three novel AIAs were evaluated in a mouse model of Trypanosoma cruzi infection, which is the causative agent of Chagas disease. The bis-AIAs DB1957, DB1959 and DB1890 were chosen based on a previous screening of their scaffolds that revealed a very promising trypanocidal effect at nanomolar range against both the bloodstream trypomastigotes (BTs) and the intracellular forms of the parasite. This study focused on both mesylate salts DB1957 and DB1959 besides the hydrochloride salt DB1890. Our current data validate the high activity of these bis-AIA scaffolds that exhibited EC50 (drug concentration that reduces 50% of the number of the treated parasites) values ranging from 14 to 78 nM and 190 to 1,090 nM against bloodstream and intracellular forms, respectively, also presenting reasonable selectivity indexes and no mutagenicity profile predicted by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET). Acute toxicity studies using murine models revealed that these AIAs presented only mild toxic effects such as reversible abdominal contractions and ruffled fur. Efficacy assays performed with Swiss mice infected with the Y strain revealed that the administration of DB1957 for 5 consecutive days, with the first dose given at parasitemia onset, reduced the number of BTs at the peak, ranging between 21 and 31% of decrease. DB1957 was able to provide 100% of animal survival, while untreated animals showed 70% of mortality rates. DB1959 and DB1890B did not reduce circulating parasitism but yielded >80% of survival rates.

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CPY3A4-Mediated Lopinavir Bioactivation and Its Inhibition by Ritonavir

Cited by 30 publications

References 31 publications

Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacsin vitro

Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacsin vitro

Role of CYP3A in Isoniazid Metabolism In Vivo

Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of <em>Trypanosoma cruzi</em> infection

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