Cocktail approach

Zhu, B., et al., "Assessment of Cytochrome P450 Activity by a Five-Drug Cocktail Approach," Clin. Pharmacol. Ther., 70, 455-461 (2001). 

Frye RF, Matzke GR, Adedoyin A, et al. Validation of the five-drug Pittsburg Cocktail approach for assessment of selective regulation of drug-... 

Koljonen, M., Hakala, K.S., Antola-Satila, T., Laitinen, L., Kostiainen, R., Kotiaho, T., Kaukonen, AM. and Hirvonen, J. (2006). Evaluation of cocktail approach to standardize Caco-2 permeability experiements. Eur. J. Pharm. Biopharm., 64, 379-387. 

Allen, M. C. Shah, T. S. Day, W. W. 1998. Rapid determination of oral pharmacokinetics and plasma free fraction using cocktail approaches methods and application. Pharm. Res., 15, 93-97. 

Dapsone (4,4 -diaminodiphenylsulfone) has been widely used for phenotyping with respect to acetylation by NAT-2 however, the drug is also N-hydroxylated. Formation of the hydroxylamine metabolite by human liver microsomes was found to be selectively mediated by CYP3A (286) this led to the development of a zero- to eight-hour urinary metabolic recovery ratio approach [dapsone hydroxylamine (dapsone + dapsone hydroxylamine)] to quantitatively assess this pathway of metabolism (287,288). Subsequently, the trait measure has been applied as part of a cocktail approach (35) in a number of studies investigating the putative role of CYP3A as a risk factor in cancer (289-291) and other disease states (288,292,293). 

Simultaneous administration of a mixture of substrates of CYP enzymes in one study (i.e., a cocktail approach ) in human volunteers is another way to valuate a drug s inhibition or induction potential (35), provided that the study is designed properly and the following factors are present (1) the substrates are specific for individual CYP enzymes, (2) there are no interactions among these substrates, and (3) the study is conducted in a sufficient number of subjects. Negative results from a cocktail study can eliminate the need for further evaluation of particular CYP enzymes. However, positive results can indicate the need for further in vivo evaluation to provide quantitative exposure changes (such as AUC and Cmax), if the initial evaluation only assessed the changes in the urinary parent to metabolite ratios. 

Fuhr U, letter A, Kirchheiner J. Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the Cocktail Approach. Clin Pharmacol Ther 2007 81 270-283. 

Tanaka E, Kurata N, Yasuhara H. How useftil is the "cocktail approach" for evaluating human hepatic drug metabolizing capacity using cytochrome P450 phenotvpins probes in vivo T Clin Pharm Ther 2003 28 157-65. 

The application of APCI-LC/MS techniques for the rapid determination of protein binding and pharmacokinetics in drug discovery were recently described by Allen et al. using a single quadrupole instrument. " A cocktail approach consisted of four experimental compounds and a control compound dosed orally at 1 mg/kg with plasma samples obtained at 0.5, 1, 2, 4, and 8h post dose. To insure reproducibility, the control compound was tested with each cocktail. This approach generated timely systemic exposure (AUC and Cmax) data on 44 test compounds in three work days, using two laboratory scientists. 

Andersson K, Hamalamen M, Malmqvist M (1999) Identification and optimization of regeneration conditions for affinity-based biosensor assays. A multivariate cocktail approach. Anal Chem 71 2475-2481... 

In addition to the recombinant vaccine presently in development, research on cocktails of monoclonal antibodies is being conducted at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Frederick, Maryland, to replace the despeciated horse serum. The cocktail approach will enhance the safety of the immunotherapy, and recombinant techniques will probably also reduce the cost of therapeutic antibody. 

J.4.2.3 Cocktail Approaches Simultaneous administration of a mixture of two or more probe substrates of CYP enzymes in one study in human volunteers is referred to as a cocktail approach. ... 

Zhu B, Ou-Yang DS, Chen XP, Huang SL, Tan ZR, He N, Zhou HH. Assessment of cytochrome P450 activity by a five-drug cocktail approach. Clin Pharmacol Ther 2001 70 455-461. 

Fig. 3. The difTerent oxidative metabolic pathways of antipyrine. hydroxymephenytoin was not affected by either treatment, nor was the metabohc ratio of sparteine/dehydrosparteine in 8 hour urine [6, 27], The results of this study have clearly illustrated that the cocktail allows the assessment of the differential effects of dmg treatment on oxidative enzyme activity. This approach could also be usefiil in new dmg development in order to assess whether or not a new compoimd will give rise to potential risks of dmg-drag interactions through induction or inhibition of dmg metabolism. Rather than performing several different studies with different (probe) dmgs, the cocktail approach should allow sufficient pertinent information to be obtained in the context of one experimental protocol.

Koljonen M, Hakala KS, Ahtola-Satila T, Laitinen L, Kostiainen R, Kotiaho T, Kaukonen AM, Hirvonen J. Evaluation of cocktail approach to standardise Caco-2 permeability experiments. Eur J Pharm Biopharm 2006 64(3) 379—387. 

---