N-in-1 dosing

He K et al (2008) N-in-1 dosing pharmacokinetics in drug discovery experience, theoretical and practical considerations. J Pharm Sci 97 2568-2580... 

Pharmacokinetic studies used to be carried out on a single compound at a time, but in order to improve throughput the concept of cassette or N-in-1 dosing was introduced. In this case, N refers to the number of co-administered compounds, often about five including a standard. Figure 9.41 shows data from a 5-in-l study in dog and clearly points out the... 

In order to expand the throughput for PK screening, cassette-dosing or N-in-1 was also employed. This cassette dosing method can provide plasma samples containing a mixure of multiple compounds. 

In order to increase throughput in pharmacokinetic screening studies, simultaneous dosing of numerous compounds followed by multiple component analysis using LC-MS/MS (the so-called N-in-1 approach) has been developed and proved to be effective [71]. 

FIGURE 6.6 Schilcl regression for pirenzepine antagonism of rat tracheal responses to carbachol. (a) Dose-response curves to carbachol in the absence (open circles, n = 20) and presence of pirenzepine 300 nM (filled squares, n = 4), 1 jjM (open diamonds, n=4), 3j.lM (filled inverted triangles, n = 6), and 10j.iM (open triangles, n = 6). Data fit to functions of constant maximum and slope, (b) Schild plot for antagonism shown in panel A. Ordinates Log (DR-1) values. Abscissae logarithms of molar concentrations of pirenzepine. Dotted line shows best line linear plot. Slope = 1.1 + 0.2 95% confidence limits = 0.9 to 1.15. Solid line is the best fit line with linear slope. pKB = 6.92. Redrawn from [5],... 

Toxicity. A 1% concn of the gas in air is lethal to rats in 1 hour, its effect being similar to C monoxide the LD50 in rats when injected intra-peritoneally is 8.2ml/kg (Ref 16). Earlier workers assumed that the toxicity of N trifluoride would be similar to H fluoride and that the latter would be formed by hydrolysis in body tissues (Ref 1). This has recently been shown to be erroneous, and that it is stable under physiological conds. The toxic effect is due to its ability to complex with the hemoglobin of the blood causing anoxia. This effect is reversible, and animals receiving a sublethal dose recover rapidly upon removal from contact with N trifluoride (Ref 14)... 

D 2-4 meg IV/SQ daily administered as a single daily dose or in two divided doses n 10-40 meg in 1-3 divided doses intranasally daily... 

In rats dosed orally with the insect repellent N,N-diethyl-2-phenylacet-amide (4.57), TV-ethyl-2-phenylacetamide (4.58), 2-phenylacetamide (4.59), and 2-phenylacetic acid (4.60) were found as metabolites in the blood, liver, and kidney [35], Hydrolysis of this tertiary amide is, perhaps, facilitated by the presence of the aromatic ring. Indeed, a similar metabolic pattern has been found for the aromatic amide TV,TV-diethyl-3-methylbenz amide (4.82) (see Sect. 4.3.1). 

A less invasive procedure that could provide a indication of DNA adduct formation is measurement in the urine of the mercaptic acid S-[2-N -guanl)ethyl]-N-acetylcysteine. Excretion of this metabolite into the urine of rats occurs in a dose-dependent, linear manner after intraperitoneal administration of 1,2-dibromoethane (Kim and Guengerich 1989). This biomarker has not been looked for to date in humans suspected to have exposure to 1,2-dibromoethane. 

When correction for differences in body size is based on body weight, the exponent n in the allometric equation is 1 and the human dose Xhuman (expressed in mg) can be calculated as follows ... 

B.5.1 Dose Equivalent and Dose Equivalent Rate. Dose equivalent or rem is a special radiation protection quantity that is used to express the absorbed dose in a manner which considers the difference in biological effectiveness of various kinds of ionizing radiation. The ICRU has defined the dose equivalent, H, as the product of the absorbed dose, D, the quality factor, Q, and all other modifying factors, N, at the point of interest in biological tissue. This relationship is expressed as follows H = D X Q X N. 

True alkaloids derive from amino acid and they share a heterocyclic ring with nitrogen. These alkaloids are highly reactive substances with biological activity even in low doses. All true alkaloids have a bitter taste and appear as a white solid, with the exception of nicotine which has a brown liquid. True alkaloids form water-soluble salts. Moreover, most of them are well-defined crystalline substances which unite with acids to form salts. True alkaloids may occur in plants (1) in the free state, (2) as salts and (3) as N-oxides. These alkaloids occur in a limited number of species and families, and are those compounds in which decarboxylated amino acids are condensed with a non-nitrogenous structural moiety. The primary precursors of true alkaloids are such amino acids as L-ornithine, L-lysine, L-phenylalanine/L-tyrosine, L-tryptophan and L-histidine . Examples of true alkaloids include such biologically active alkaloids as cocaine, quinine, dopamine, morphine and usambarensine (Figure 4). A fuller list of examples appears in Table 1. 

Uses Severe, systemic fungal Infxns oral cutaneous candidiasis Action Binds ergosterol in the fungal membrane to alter permeability Dose Adults Peds. Test dose 1 mg IV adults or 0.1 mg/kg to 1 mg IV in children then 0.25-1.5 mg/kg/24 h IV over 2-6 h (range 25-50 mg/d or qod). Total dose varies w/ indication PO 1 mL qid Caution [B, ] Disp Inj SE -1- K /Mg from renal wasting anaphylaxis reported, HA, fever, chills, n hrotox, -1- BP, anemia, rigors Notes -1- In renal impair pre-Tx w/ APAP antihistamines (Benadryl) X SE Interactions T Nephrotoxic effects W/ antineoplastics, cyclosporine, furosemide, vancomycin, aminoglycosides, T hypokalemia W/ corticost oids, skeletal muscle relaxants EMS May cause electrolyte imbalances, monitor ECG OD May effect CV and resp Fxn symptomatic and supportive... 

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