Towards new transmission-blocking combination therapies - pharmacokinetics of 10-amino-artemisinins and 11-aza-artemisinin, and comparison with DHA and artemether

As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug and third drug with different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins and 11-aza-artemisinin, and conduct ADME profiling in vitro and PK profiling in vivo via iv and po administration to mice. The sulfamide derivative has a notably long murine microsomal half-life ( t 1/2 >150 min), low intrinsic liver clearance and total plasma clearance rates ( CL int 189.4, CL tot 32.2 mL/min/kg), and high relative bioavailability (F 59%). Kinetics are somewhat similar for 11-aza-artemisinin ( t 1/2 >150 min, CL int 576.9, CL tot 75.0 mL/min/kg), although bioavailability is lower (F 14%). In contrast, artemether is rapidly metabolized to DHA ( t 1/2 17.4 min) and eliminated ( CL int 855.0, CL tot 119.7 mL/min/kg), and has low oral bioavailability F of 2%. Whilst artemisone displays low t 1/2 of <10 min and high CL int of 302.1, it displays a low CL tot of 42.3 mL/min/kg, and moderate bioavailability F of 32%. Its active metabolite M1 displays a much improved t 1/2 of >150 min and a reduced CL int of 37.4 mL/min/kg. Artemiside has t 1/2 12.4 min and CL int 673.9 and CL tot 129.7 mL/kg/min, likely a reflection of its surprisingly rapid metabolism to artemisone, reported here for the first time. DHA is not formed from any amino-artemisinin. Overall, the efficacy and PK data strongly support the development of selected amino-artemisinins as components of new TACTs.

Impact of the Herbal Breviscapine on the Pharmacokinetics of Simvastatin in Rats: The Involvement of CYP3A4

The effect of breviscapine injection on the pharmacokinetics of simvastatin and the mRNA expression of hepatic cytochrome P450 (CYP) enzyme was investigated with rats. The rats were pretreated for 8 consecutive days with breviscapine injection (20 mg/kg/day, i. v.), followed by administration of simvastatin through gavage (40 mg/kg). The control rats received the corresponding volume of saline solution for the pretreatment. Blood samples were collected at varied time points after simvastatin administration and the liver was harvested after the last collection of the blood sample for measurement of the CYP3A4 mRNA expression. Pre-treatment with breviscapine injection led to increased plasma concentration of simvastatin, showing 57% increase for AUC0-∞ (P<0.01), 31% increase for C max (P<0.01), and 36% decrease for the total plasma clearance, compared with the control. Pre-treatment with breviscapine injection also inhibited the mRNA expression of the hepatic CYP3A4. These findings indicate that pre-treatment with breviscapine injection could increase the plasma concentration of simvastatin, possibly by inhibiting the expression of the hepatic CYP3A4, and combined use of breviscapine with simvastatin may improve the simvastatin efficacy and reduce its adverse reactions through reduced its dosage.

Evaluation of single sample clearance calculations in 902 patients

Purpose: To derive new formulae for the calculation of single sample clearance of the contrast medium iohexol and to compare the formulae to a selection of existing single sample clearance formulae derived for the calculation of 51Cr-EDTA and 99mTc-DTPA clearance. Material and Methods: Glomerular filtration rate (GFR) was calculated from total plasma clearance of iohexol used for urography in 902 patients. Two plasma samples were drawn in each patient. Automated x-ray fluorescence analysis equipment was used for the plasma iodine analysis. Single and multiple sample iohexol clearance values were compared. In 77 patients the multiple sample clearance values were additionally compared to a 51Cr-EDTA clearance performed simultaneously or within 14 days. Results: The precision of the results calculated by the existing single sample clearance formulae and the derived iohexol single sample clearance formulae were essentially the same. The most precise of the derived formulae was that based on the Bak Christensen & Groth formula. The correlation between multiple sample clearance of iohexol and 51Cr-EDTA was high (r=0.918) Conclusion: Iohexol can substitute 51Cr-EDTA for GFR measurement. A valid GFR can be calculated from a single plasma sample determination of iohexol clearance using either the existing formulae or the new formulae derived from the present study.

Experimental Studies Comparing Iohexol and 51Cr-Edta for Glomerular Filtration Rate Measurements

The total plasma clearance as well as the renal clearance of iohexol were evaluated for determination of the glomerular filtration rate (GFR) in 16 anesthetized pigs. The iohexol levels in urine and plasma were measured by X-ray fluorescence. The total plasma clearance of 1 and 4 ml/kg b.w. of iohexol 300 mg I/ml was compared to the simultaneously as well as nonsimultaneously calculated total plasma clearance of 51Cr-EDTA. The total plasma clearance of 51Cr-EDTA and of iohexol turned out to be equal and independent of the injected dose of iohexol. The injected dose did not have any effect on the renal clearance of iohexol either. It is concluded that iohexol and 51Cr-EDTA are similar as marker substances for determination of the GFR.

Simultaneous Urography and Determination of Glomerular Filtration Rate

The total plasma clearance of iohexol at urography and 51Cr-EDTA was compared in 31 patients with di- or tetraparesis. A reference 51Cr-EDTA clearance was also performed 24 hours prior to the urography. The GFR was calculated from one, 2 or 4 plasma samples collected 180, 210, 240 and 270 min after the injection. An X-ray fluorescence analyzer was used for the analysis of iohexol in plasma as well as the contrast medium clearance calculations. It was shown that single or multiple sample clearance of iohexol and 51Cr-EDTA were equivalent methods for measurement of the GFR. The GFR was not affected by iohexol in a dose routinely used for urography. It was concluded that the patient comfort is improved if 51Cr-EDTA clearance is replaced by contrast medium clearance in association with urography.

Glomerular Filtration Rate Estimated after Multiple Injections of Contrast Medium during Angiography

In twenty-six patients referred for angiography, clearance of contrast medium was determined with x-ray fluorescence analysis after multiple injections of contrast medium. A formula for correction of the injected amount, which takes into consideration the different times of contrast medium injections, approximating the total injected amount into one injection, was used. A single injection clearance of 51Cr-EDTA was determined at the same time. The results showed a good correlation between the clearance of contrast medium after multiple injections and the 51Cr-EDTA clearance after a single injection (r=0.945). The correlation between contrast medium clearance calculated without correction for the different injection times, and “Cr-EDTA clearance was the same (r=0.946), due to short angiography time and rather low clearance values in our patients. It is concluded that total plasma clearance of contrast medium can easily be estimated after multiple injections. In this way patients with a risk of developing post-angiographic renal failure can be found.