Plasma metabolic ratios

Sohn DR, Kusaka M, Shin SG, et al. Utility of a one-point (3-hour postdose) plasma metabolic ratio as a phenotyping test using metoprolol in two East Asian populations. Ther Drug Monit 1992 14 184—189. 

These findings explain some pharmacokinetic interactions of clobazam with ketoconazole (which inhibits the demethy-lation of clobazam by 70%) and omeprazole (which inhibits the hydroxylation of N-desmethylclobazam by 26%). In addition, in 22 patients with epilepsy who were genotyped for CYP2C19, there was a higher plasma metabolic ratio of N-desmethylclobazam clobazam in patients with one CYP2C19 2 mutated allele than in those with the wild-type genotype. 

It is also possible to determine a single time-point, dextromethorphan metabolic ratio in plasma within 2-5 hr after an oral dose or in a 6-hr saliva sample (229,230) however, neither of these alternative approaches has been widely used. 

Metabolic ratios (MR) used are plasma 17X/137X and urinary (1U + IX + AFMU)/17U. 

Assays have been developed to determine DM and DX in plasma or saliva (Bolden et al. 2002 Hu et al 1998 Chladek et al. 2000 Hartter et al. 1996). The use of saliva or plasma for CYP2D6 phenotyping has been developed for subject convenience, or for the development of single point methods to be easily incorporated in the cocktail methods . Good correlation between metabolic ratios calculated from plasma, saliva samples and those obtained from urine have been observed. 

At the other extreme of the absorption rate spectrum, when the absorption rate is high and portal vein concentrations are high, the presentation rates of the enantiomers to the liver exceed the maximum velocities (V ) of their metabolic pathways. This scenario results in saturation of the metabolic enzymes and large, and approximately equal, fractions of both enantiomers will pass through the liver unchanged, and the R S bioavailability ratio will approach 1 1. Given the difference in the enantiomer volumes of distribution, this will produce an R S plasma concentration ratio of approximately 2 1, just as is observed following intravenous administration. 

In addition, observations that various tumor characteristics (e.g., TS expression), patient drug-metabolizing enzymes (e.g., DPD and plasma uracihdihydrouracil ratio), and molecular markers (e.g., chromosome 18q allelic loss, microsatellite instability, and p53 muta-... 

Stereoselective metabolism is the most important process responsible for the stereoselectivity observed in pharmacokinetics. Verapamil has received considerable attention as an example of substrate stereoselective pharmacokinetics in humans. After oral administration, the drug undergoes an important stereoselective first pass metabolism, so that (— )-verapamil, the active enantiomer, has a two to three times lower bioavailability than its antipode. The (— )/(-f) plasma concentration ratio is therefore higher after intravenous than after oral administration. 

It has been suggested [60,61] that the rate of input of chiral drugs after the oral administration may affect the stereoselectivity in their pharmacokinetics. Simulations [60] have shown that drugs with Michaelis-Menten type first-pass metabolism whose input rate approaches the maximum rate of metabolism (Fmax) of the enantiomers are most susceptible to this phenomenon. A study [151] in isolated perfused rat livers demonstrated that when the input rate of racemic verapamil was doubled, the stereoselectivity in the outlet concentration of the drug was lost. In humans, Karim and Piergies [152] showed that the R S plasma concentration ratios of verapamil at maximum plasma concentration (Cmax) were formulation dependent a sustained release formulation resulted in lower total concentrations at time to reach C ax ( max), associated with higher R S ratios, when compared with an immediate release formulation (Fig. 8). Similar input rate-dependent stereoselective pharmacokinetics of verapamil have also been suggested by others [146,153]. 

A classic method of demonstrating enantioselective first-pass metabolism is to administer the racemic drug orally and i.v. in a crossover study and then evaluate the PK of each enantiomer using a stereospecific assay. Stereoselective first-pass metabolism is indicated by significantly different absolute bioavailabilities of the enantiomers. This approach was used to establish low enantioselective first-pass metabolism of ketoprofen [56] and high enantioselectivity of propranolol [38,42] and verapamil [44,45,53]. Enantioselective metabolism of propranolol and verapamil has been studied extensively and found to be influenced by age and gender [40,50]. With verapamil, changes in plasma enantiomeric ratios after administration... 

Diazepam is converted metabolically to N-desmethyldia-zepam. A study of the relationship between blood, brain and adipose tissue has been carried out for the two compounds in mice. Blood and brain concentrations of diazepam decreased from the time of administration, whereas adipose tissue concentrations reached a maximum at 30 minutes. The metabolite (N-desmethyldiazepam) showed a growth and decay pattern in blood with a peak at 60 minutes. The brain concentration followed a similar time course, but the adipose tissue concentration reached its peak considerably later. This peak was also later than that of diazepam, and the tissue-to-plasma concentration ratios were less for the metabolite in comparison with those for diazepam. Note that the peak drug concentration is achieved within 1 hour, whereas the peak concentrations of the metabolite occur at 8-10 hours post dosing. 

Accurate, precise isotope ratio measurements are important in a wide variety of applications, including dating, examination of environmental samples, and studies on drug metabolism. The degree of accuracy and precision required necessitates the use of special isotope mass spectrometers, which mostly use thermal ionization or inductively coupled plasma ionization, often together with multiple ion collectors. 

Interestingly, it has been shown that supplementation of greenfinches with lutein and zeaxanthin at a ratio of 20 1 increases plasma levels of triglycerides and bird body mass (Horak et al., 2006). These data suggest that xanthophylls may affect lipid metabolism. 

Above 5 Low solubility and poor oral bioavailability. Erratic absorption. High metabolic liability, although potency may still be high. Basic amines tend to show high to very high Vd (Volume of distribution = ratio of overall tissue binding to plasma protein binding)... 

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