Phenotyping of CYP 4501A2 Activity by Total Overnight Salivary Caffeine Assessment (TOSCA) in Patients on Warfarin Treatment: A Cross-Sectional Study

Abstract

Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow therapeutic index, widespread individual variability in clinical response, and high rates of adverse events, particularly bleeding complications. For these reasons, a close monitoring of the dosage, using the frequent assessment of coagulation status by means of International Normalized Ratio value, is mandatory. Warfarin is metabolized by hepatic cytochrome P-450. High CYP 450 activity may lead to low drug concentration and requires high warfarin doses to reach efficacy; conversely, low CYP 450 activity is responsible for high drug concentration and needs for low doses to avoid potential toxicity risks. The major isoforms of CYP involved in the metabolism of warfarin sodium are CYP1A2 (for the R-warfarin) and CYP2C9 (for the S-warfarin). The probes for testing CYP1A2 are phenacetin and caffeine while for CYP2C9 tolbutamide. Although S-warfarin has major activity, it was decided to exclude its phenotyping for ethical issues, being mandatory to use a drug (tolbutamide). Instead, it was chosen to test the 1A2 isoform, as the activity of the latter isoform could be investigated by using caffeine contained in the caffeinated beverages. Specifically, a single-point concentration of salivary caffeine (total overnight salivary caffeine assessment [TOSCA]) after an overnight period of the caffeinated beverages abstinence was utilized. In the present study, 75 nonsmoker patients regularly receiving warfarin sodium were enrolled. The results have showed a significant association of the warfarin dose with TOSCA values (coefficient = -0.15, standard error = 0.04, 95% confidence interval = -0.24 to -0.06, t = -3.23, P = .002). In conclusion, the phenotyping of CYP1A2 by TOSCA could be useful, if further proven, to help manage patients on warfarin in order to lessen severe adverse events.

The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention

“…The variants of cytochrome P450 and paraoxonase can lead to the change of enzyme activity, especially the mutation of CYP2C19*2, CYP2C19*3, PONQ192R allelic [17,18]. The probe drug could be used to measure the activity of CYP450 and to point out the genotyping of CYP450 [19]. Ersin Gumus etal evaluate lansopranzole as an in vivo phenotyping probe for assessing CYP2C19 activity, they found that the poor metabolizers have lower enzyme activity [20].…”

Precision sirolimus dosing in children: The potential for model-informed dosing and novel drug monitoring

“…For TDM, unstimulated saliva samples were collected by expectorating or with the help of a saliva collection device such as Salivette ® (Sarstedt, Nümbrecht, Germany). In some cases, saliva excretion is stimulated by paraffin wax ( Cohen et al, 1985 ; Tarantino et al, 2018 ) or citric acid ( Kirk et al, 1994 ; Kopecky et al, 1997 ) and collected by similar methods. For younger children, saliva collection is usually performed with the help of an adult and a variety of devices and collection methods to facilitate sample collection.…”