Chen Hong-zhuan

Limited sampling strategy for the estimation of mycophenolic acid area under the plasma concentration-time curve in adult patients undergoing liver transplant.

Mycophenolate mofetil (MMF), the oral prodrug of mycophenolic acid (MPA), is increasingly used in liver transplantation and plays a central role in the immunosuppressive regimen in liver transplantation. To study pharmacokinetic-pharmacodynamic relationships and therapeutic drug monitoring of MPA in the clinical setting, limited sampling strategies have been investigated for the estimation of MPA areas under the curves (AUCs). Thirty-eight adult patients undergoing liver transplant (31 males, seven females) receiving 1.0 g MMF twice daily and concomitant tacrolimus provided a total of 72 pharmacokinetic profiles. Multiple stepwise regression analysis was used to determine the algorithms for limited sampling strategies. Twenty-eight one-, two-, three-, and four-sampling estimation models were fitted (r2 = 0.288-0.964) to all the profiles using linear regression and were used to estimate MPA AUC0-12h comparing those estimates with the corresponding AUC0-12h values calculated with the linear trapezoidal rule, including all 10 timed MPA concentrations. The four-point estimates at C1h, C2h, C6h, and C8h resulted in the best correlation between estimated AUC and true AUC when using the formula AUC = 6.03 + 0.89C1h + 1.94C2h + 2.24C6h + 4.64 C8h (r2 = 0.911). Bland and Altman analysis revealed good agreement between estimated AUC and AUC from the full profile. This limited sampling strategy provides an effective approach for estimation of full MPA AUC0-12h in patients undergoing liver transplant receiving concomitant tacrolimus therapy.

Evaluation of the practicability of limited sampling strategies for the estimation of mycophenolic acid exposure in Chinese adult renal recipients.

The immunosuppressive potential of mycophenolic acid (MPA) correlates well with MPA exposure [area under the concentration-time curve (AUC)]. Monitoring MPA AUC is important and helpful for maintaining the efficacy of mycophenolate mofetil while minimizing its side effects, but full MPA AUC monitoring is laborious, cost prohibitive, and impractical. Limited sampling strategies have been proposed as an alternative method for estimating MPA exposure. The objective of this study was to evaluate the practicability of different limited sampling strategies for the estimation of MPA exposure. A total of 56 pharmacokinetic profiles from 53 adult renal recipients were used to evaluate the practicability of 10 published models. Standard correlation and linear regression analysis were used to compare the estimated MPA AUCs and corresponding full MPA AUCs, and the percentage of profiles for which prediction error fell within ±20% was also used to assess the practicability of these models. Agreement between the estimated MPA AUCs and full MPA AUCs was further tested by Bland and Altman analysis. The model, based on four sampling time points, used the formula AUC = 12.61 + 0.37 × C0.5 + 0.49 × C1 + 3.22 × C4 + 8.17 × C10, was superior to all other evaluated models, with the highest coefficient of determination (r2 = 0.88), a low percentage prediction error (2.79%), and good agreement according to Bland and Altman analysis. Prediction errors of 87.5% (49/56) of profiles were within 20%, which was the highest of all the models. This algorithm can be reliably used for estimating MPA exposure in adult renal transplant patients treated with cyclosporine as concomitant immunosuppressant. Another model based on the formula AUC = 8.22 + 3.16 × C0 + 0.99 × C1 + 1.33 × C2 + 4.18 × C4 also has acceptable predictive performance, and it may also be practical, especially in outpatient settings, in view of its distribution of time points.

Muscarinic acetylcholine receptor modulators derived from natural toxins and diverse interaction modes

Muscarinic acetylcholine receptors (mAChRs) play crucial roles in various physiological functions and pathophysiological processes. Acetylcholine (ACh), as a classical ligand and one of the pivotal neurotransmitters, serves as a prototype for the elucidation of molecular interaction and the development of mimicked and antagonized agents. With the advances in medicinal chemistry and structural biology, more and more mAChRs modulators derived from natural toxins have been identified. Based on the chemical structures and the receptor-ligand interaction modes, these mAChRs modulators can be divided into orthosteric modulators, allosteric modulators and other modulators. Moreover, allosteric modulators can be further divided into three groups: alcuronium-like modulators, staurosporine-like modulators, and phlegmarine-like modulators. In this review, we focus on various mAChRs modulators derived from natural toxins on the basis of the receptor-ligand interaction modes. The understanding of the affinity, the intrinsic efficacy, and the selectivity of mAChRs modulators may lead to the discovery of new drug leads for the treatment of diseases related to mAChRs.