Turnover of membrane proteins: Kinetics of induction and degradation of seven forms of rat liver microsomal cytochrome P-450, NADPH-cytochrome P-450 reductase, and epoxide hydrolase

Shiraki, Hiroshi; Guengerich, F. Peter

doi:10.1016/0003-9861(84)90257-1

Cited by 98 publications

(36 citation statements)

References 33 publications

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“…4B) assuming a zero order rate for CYP3A synthesis that is unaffected by ERY administration and a first-order rate of enzyme degradation. Our estimate is within the range of CYP3A elimination rate constants in rats (0.0348 -0.072 h Ϫ1 ) estimated in previous studies (Shiraki and Guengerich, 1984;Correia, 1991). An accurate estimation of the degradation rate constant is critical for the prediction of the extent and time course of irreversible inhibition in vivo (Mayhew et al, 2000;Zhang et al, 2009;Zhang et al, 2009).…”

Section: Discussionsupporting

confidence: 77%

Inhibition of CYP3A by Erythromycin: In Vitro-In Vivo Correlation in Rats

et al. 2009

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ABSTRACT:The prediction of in vivo drug-drug interactions from in vitro enzyme inhibition parameters remains challenging, particularly when time-dependent inhibition occurs. This study was designed to examine the accuracy of in vitro-derived parameters for the prediction of inhibition of CYP3A by erythromycin (ERY). Chronically cannulated rats were used to estimate the reduction in in vivo and in vitro intrinsic clearance (CL int ) of midazolam (MDZ) after single and multiple doses of ERY; in vitro recovery of CL int was determined at 1, 2, 3, and 4 days after discontinuation of ERY. Enzyme inhibition parameters (k inact , K I , and K i ) of ERY were estimated in vitro by using untreated rat liver microsomes. In vivo enzyme kinetic analysis indicated that single and multiple doses of ERY (150 mg/kg i.v. infusion over 4 h) reduced MDZ CL int by reversible and irreversible mechanisms, respectively. CYP3A inactivation after multiple doses of ERY treatment reflected metabolic intermediate complex formation without a significant change in hepatic CYP3A2 mRNA. A physiologically based pharmacokinetic model of the interaction between ERY and MDZ predicted a 2.6-fold decrease in CYP3A activity after repeated ERY treatment using in vitro-estimated enzyme inhibition parameters and in vivo degradation half-life of the enzyme (20 ؎ 6 h). The observed -fold decreases were 2.3-fold and 2.1-fold for the in vitro-estimated CYP3A activity and the in vivo CL int , respectively. This study demonstrates that in vivo DDIs are predictable from in vitro data when the appropriate model and parameter estimates are available.The prediction of in vivo drug-drug interactions (DDIs) from in vitro data has met with limited success, and the general applicability of such predictions is unclear (von Moltke et al., 1998;Wang et al., 2004;Obach et al., 2005Obach et al., , 2007. As drugs capable of mechanismbased inhibition (MBI) have emerged as clinically important CYP3A inhibitors (Zhou et al., 2004), the uncertainty in predictive accuracy has increased. Approaches to predicting MBI-based DDIs vary from a relatively simple method using a single-inhibitor concentration to more complicated physiologically based pharmacokinetic (PBPK) models that consider the change of inhibitor and substrate concentrations with time (Mayhew et al., 2000;Ito et al., 2003;Wang et al., 2004;Obach et al., 2007). Changes in the amount of active enzyme in the presence of a mechanism-based inhibitor are estimated by using the in vitro enzyme inactivation parameters, K I and k inact , which can be used to predict the increase in the in vivo exposure of the substrate. These predictions often suffer from poor characterization of substrate and inhibitor properties in vitro and/or in vivo and from uncertainties in predictive model parameter values. For example, DDIs may reflect simultaneous reversible inhibition, irreversible inhibition, and induction at multiple sites of enzyme expression, but the relative contribution of each type of interaction in vivo may be difficult to d...

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Section: Discussionsupporting

confidence: 77%

Inhibition of CYP3A by Erythromycin: In Vitro-In Vivo Correlation in Rats

et al. 2009

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“…The attenuation in the expression of CYP1A1/1A2 apoprotein between 48 and 72 h of hyperoxia may also have involved other mechanisms. The half-life of CYP1A1/1A2 proteins is reported to be 16 h (Shiraki and Guengerich, 1984). Therefore, the decline of apoprotein content and activities between 48 and 72 h may have been due to loss of immunoreactivity or function via oxidative degradation of CYP1A1/ 1A2 by hyperoxia.…”

Section: Role Of the Ah Receptor In Hyperoxic Lung Injury 517mentioning

confidence: 99%

Disruption of the Ah Receptor Gene Alters the Susceptibility of Mice to Oxygen-Mediated Regulation of Pulmonary and Hepatic Cytochromes P4501A Expression and Exacerbates Hyperoxic Lung Injury

Jiang¹,

Welty²,

Couroucli³

et al. 2004

J Pharmacol Exp Ther

109

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Administration of supplemental oxygen is frequently encountered in infants suffering from pulmonary insufficiency and in adults with acute respiratory distress syndrome. However, hyperoxia causes acute lung damage in experimental animals. In the present study, we investigated the roles of the Ah receptor (AHR) in the modulation of cytochrome P4501A (CYP1A) enzymes and in the development of lung injury by hyperoxia. Adult male wild-type [AHR (ϩ/ϩ)] mice and AHR-deficient animals [AHR (Ϫ/Ϫ)] were maintained in room air or exposed to hyperoxia (Ͼ95% oxygen) for 24 to 72 h, and pulmonary and hepatic expression of CYP1A and lung injury were studied. Hyperoxia caused significant increases in pulmonary and hepatic CYP1A1 activities (ethoxyresorufin O-deethylase) and mRNA levels in wild-type (C57BL/6J) AHR (ϩ/ϩ), but not AHR (Ϫ/Ϫ) mice, suggesting that AHR-dependent mechanisms contributed to CYP1A1 induction. On the other hand, hyperoxia augmented hepatic CYP1A2 expression in both wild-type and AHR (Ϫ/Ϫ) animals, suggesting that AHR-independent mechanisms contributed to the CYP1A2 regulation by hyperoxia. AHR (Ϫ/Ϫ) mice exposed to hyperoxia were more susceptible than wildtype mice to lung injury and inflammation, as indicated by significantly higher lung weight/body weight ratios, increased pulmonary edema, and enhanced neutrophil recruitment into the lungs. In conclusion, our results support the hypothesis that the hyperoxia induces CYP1A1, but not CYP1A2, expression in vivo by AHR-dependent mechanisms, a phenomenon that may mechanistically contribute to the beneficial effects of the AHR in hyperoxic lung injury.

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“…The average turnover rate constant (k deg ) of rat P450 (0.0005 min Ϫ1 ) (Shiraki and Guengerich, 1984) was used in the present simulation because the corresponding value for human CYP3A has not been reported. When the minimum reported value of k deg (0.00033 min Ϫ1 ) was used, almost the same results were obtained for clarithromycin and azithromycin, whereas the predicted degree of in vivo interaction was increased in the case of erythromycin, compared with using the k deg of 0.0005 min Ϫ1 (Table 5).…”

Section: Ito Et Almentioning

confidence: 99%