Pharmacokinetics of oral noscapine

Karlsson, Mats O.; Dahlström, Bengt; Eckernäs, S.‐Å.; Johansson, Margareta; Alm, Agneta Tufvesson

doi:10.1007/bf00315110

Cited by 95 publications

(88 citation statements)

References 15 publications

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“…Testis showed the highest expression of the 1.35 kb mRNA and there was no indication of a 1 kb band. This pattern of expression is clearly different from that of human dCK, which showed the highest level of a 2.8 kb mRNA in spleen and thymus [18].…”

Section: Resultscontrasting

confidence: 76%

“…When the dGK sequence was used in a BLAST search against the GenBank nucleotide sequence data base the best matches were to human [9], mouse [18] and rat [19] deoxycytidine kinase sequences. The similarity in the deduced protein sequence were overall 46% and in some regions as high as 70%.…”

Section: Discussionmentioning

confidence: 99%

“…Basic amino acids presumably involved in mitochondrial localization signal for dGK are underlined. Residues marked with * indicates regions of conservation with other members of the deoxynucleoside kinases [18][19][20][21][22][23][24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

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Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA

1996

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Mammalian mitochondrial deoxyguanosine kinase (dGK) is responsible for phosphorylation of purine deoxyribonucleosides in the mitochondrial matrix. Using a RT-PCRgenerated probe, based on amino acid sequence information from proteolytic fragments of purified bovine dGK, we have cloned a cDNA from a human brain cDNA library that encodes a 30 kDa protein. The deduced amino acid sequence of this protein included the sequence of all six peptides isolated and sequenced from purified dGK. Expression and purification of recombinant protein from induced Escherichia coli extracts revealed that it catalyses efficient phosphorylation of dGuo, arabinosyl guanine, dAdo, 2-chloro-2'-deoxyadenosine and dlno similar to purified dGK. Northern blot analysis demonstrated one dominant positive mRNA of 1.35 kb and it was found in several tissues at similar levels. The coding sequence of dGK showed 46% identity to the coding sequence of cytosolic deoxycytidine kinase, and conserved sequence motifs among the known deoxynucleoside kinase were identified.

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Section: Resultscontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA

1996

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“…Lineweaver-Burk and Dixon plots suggested that noscapine competitively inhibited CYP3A4 and the Ki value was evaluated to be 5.2 mM. Employing the above data and maximum concentration of noscapine (Cmax) after a single 50-mg oral dose (0.15 mM) [19], the AUC of (S)-warfarin and (R)-warfarin was predicted to increase by 1.5% and 1.1%, respectively. Considering the effect of human serum binding of noscapine (fu = 35% [20]), the AUC of (S)-warfarin and (R)-warfarin was predicted to increase by 0.5% and 0.4%, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…KI,u was calculated to be 6.1 mM and 5.9 mM for CYP3A4 and CYP2C9, respectively. With KI,u, kinact and maximum concentration of noscapine (Cmax) after a single 50-mg oral dose (0.15 mM) [19], the AUC of (S)-warfarin and (R)-warfarin was calculated to increase by 110.9% and 48.9%, respectively. When the human serum binding of noscapine (fu = 35% [20]) was considered, the AUC of (S)-warfarin and (R)-warfarin was predicted to increase by 41.8% and 32.7%, respectively.…”

Section: Resultsmentioning

confidence: 99%

Time‐dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

Fang

Zhang

et al. 2010

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Clinical cases reported to the Swedish adverse drug interactions register (SWEDIS) indicated that drug-drug interaction (DDI) existed when warfarin was co-administered with noscapine.• In vitro testing with recombinant human enzyme showed that noscapine inhibited CYP3A4 and CYP2C9 with an IC50 of around 1 mM.• However, the clinical relevance of these in vitro data remains to be explored. WHAT THIS STUDY ADDS• Noscapine was demonstrated to be both a reversible inhibitor and a time-dependent inhibitor to CYP3A4 and CYP2C9.• DDI magnitude predicted from reversible inhibition and time-dependent inhibition (TDI) kinetic parameters showed that the TDI might be a noteworthy factor resulting in clinical noscapine-warfarin interaction. AIMSTo investigate the inhibition potential and kinetic information of noscapine to seven CYP isoforms and extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data. METHODSThe activities of seven CYP isoforms (CYP3A4, CYP1A2, CYP2A6, CYP2E1, CYP2D6, CYP2C9, CYP2C8) in human liver microsomes were investigated following co-or preincubation with noscapine. A two-step incubation method was used to examine in vitro time-dependent inhibition (TDI) of noscapine. Reversible and TDI prediction equations were employed to extrapolate in vivo noscapine-warfarin interaction magnitude from in vitro data. RESULTSAmong seven CYP isoforms tested, the activities of CYP3A4 and CYP2C9 were strongly inhibited with an IC50 of 10.8 Ϯ 2.5 mM and 13.3 Ϯ 1.2 mM. Kinetic analysis showed that inhibition of CYP2C9 by noscapine was best fit to a noncompetitive type with Ki value of 8.8 mM, while inhibition of CYP3A4 by noscapine was best fit to a competitive manner with Ki value of 5.2 mM. Noscapine also exhibited TDI to CYP3A4 and CYP2C9. The inactivation parameters (KI and kinact) were calculated to be 9.3 mM and 0.06 min -1 for CYP3A4 and 8.9 mM and 0.014 min -1 for CYP2C9, respectively. The AUC of (S)-warfarin and (R)-warfarin was predicted to increase 1.5% and 1.1% using Cmax or 0.5% and 0.4% using unbound Cmax with reversible inhibition prediction equation, while the AUC of (S)-warfarin and (R)-warfarin was estimated to increase by 110.9% and 48.9% using Cmax or 41.8% and 32.7% using unbound Cmax with TDI prediction equation. CONCLUSIONSTDI of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine-warfarin interaction.

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Time‐Dependent Inhibition

2000

Enzymes

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Pharmacokinetics of oral noscapine

Cited by 95 publications

References 15 publications

Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA

Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA

Time‐dependent inhibition (TDI) of CYP3A4 and CYP2C9 by noscapine potentially explains clinical noscapine–warfarin interaction

Time‐Dependent Inhibition

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