Urinary excretion of heptanones, heptanoles and 2,5-heptanedione after controlled acute exposure of volunteers to n-heptane.

A lack of well-established parameters and assessment values currently impairs biomonitoring of n-heptane exposure. Using controlled inhalation experiments, we collected information on urinary n-heptane metabolite concentrations and the time course of metabolite excretion. Relationships between external and internal exposure were analysed to investigate the suitability of selected metabolites to reflect n-heptane uptake. Twenty healthy, non-smoking males (aged 19-38 years, median 25.5) were exposed for 3 h to 167, 333 and 500 ppm n-heptane, each. Spot urine samples of the volunteers, collected before exposure and during the following 24 h, were analysed for heptane-2-one, 3-one, 4-one, 2,5-dione, 1-ol, 2-ol, 3-ol, and 4-ol using headspace solid phase dynamic extraction gas chromatography/mass spectrometry (HS-SPDE-GC/MS). Starting from median pre-exposure concentrations between <0.5 (3-one) and 82.9 µg/L (4-one), exposure increased the concentrations for all parameters except for 4-one. Median post-exposure concentrations ranged up to 840.4 µg/L (2-ol) and decreased with half-lifes <3 h after exposure. Non-parametric correlation analyses (n = 47, p < 0.05) revealed weak to moderate associations of volume related metabolite excretion with external exposure for 2-one, 3-one and 2,5-dione (R = 0.332-0.753). Heptanol excretion was moderately associated with exposure (R ≥ 0.509) only after creatinine adjustment. Lacking association with external exposure impedes the use of 4-one as heptane biomarker, whereas 2-ol and 3-ol turned out to be sensitive indicators of exposure if creatinine correction is applied. By providing fundamental data on a panel of eight potential heptane metabolites, our study can help to promote biological monitoring of n-heptane exposure.

Chirality in anesthesia I: minimum alveolar concentration of secondary alcohol enantiomers.

Most studies of chirality in inhaled anesthetic action have used the enantiomers of isoflurane. These enantiomers are expensive and scarce, which limits studies, such as the preliminary identification of molecular targets of anesthetic action, that can be performed with these isomers. We hypothesized that secondary alcohols (i.e., compounds having a -CH2-CHOH-CH3 group) that are experimental anesthetics would show enantioselectivity. To test this hypothesis, we determined the minimum alveolar anesthetic concentration (MAC) of the enantiomers of the homologous series of 2-alcohols from 2-butanol to 2-heptanol in rats. Because these alcohols are partially metabolized to 2-ketones during the course of study (i.e., having a -CH2-CO-CH3 group), we independently measured the MAC of the 2-ketones. Assuming additivity of MAC of the ketones with the alcohols, we corrected for the anesthetic effect of the ketones in rats to determine the MAC of the alcohols. We found that the 2-butanol and 2-pentanol isomers were enantioselective. S-(+)-2-butanol had a MAC that was 17% larger than for the R-(-)-enantiomer, whereas S-(+)-2-pentanol had a MAC that was 38% larger than the R-(-)- enantiomer. No stereoselectivity was observed for 2-hexanol and 2-heptanol. These findings may permit studies of chirality in anesthesia, particularly in in vitro systems where metabolism does not occur, using inexpensive volatile compounds.

Disposition of short-chain aliphatic alcohols in rabbit vitreous by ocular microdialysis.

Anatomic and physiological barriers limit drug delivery to the posterior segment of the eye via topical or systemic administration. Intravitreal administration has proven to be a safe and effective means of treating various posterior segment diseases. Elimination of a compound from the vitreous chamber may depend on lipophilicity, diffusivity, and aqueous solubility. This information is critical for optimizing intravitreal dosing which in turn can aid in the design of drug delivery systems. The purpose of this study is to determine the vitreous disposition of an ascending homologous series of short chain aliphatic alcohols ranging from hydrophilic methanol to lipophilic 1-heptanol by microdialysis. Radiolabelled 14C-methanol, 14C-1-propanol, 14C-1-pentanol, and 14C-1-heptanol with log partition coefficient values ranging from -0.77 to 2.7 were studied. Microdialysis probes were implanted in both anterior and vitreous chamber of the rabbit eye to sample aqueous and vitreous humors simultaneously. Concentric probe was implanted in vitreous chamber about 3mm below the cornealscleral limbus. Linear probe was implanted in the anterior chamber using a 25-guage needle. Isotonic phosphate buffer saline (IPBS) (pH 7.4) was perfused through the probe with a flow rate of 2 microlml(-1). Alcohols (2.0 microg-130.72 microg) were injected into the vitreous body. In vitro recovery for the probes was calculated using respective alcohols in IPBS. Pharmacokinetic parameters were determined by non-compartmental analysis. Vitreal elimination half-lives of methanol, 1-propanol, 1-pentanol and 1-heptanol are 52.0+/-5.7, 58.5+/-5.8, 72.9+/-5.8 and 153.7+/-21.6 min, respectively. Dose normalized area under the aqueous concentration time curve values of methanol, 1-propanol and 1-pentanol are 33.8+/-13.4, 28.3+/-11.9 and 29.2+/-4.9 microgminml(-1)microg(-1)10(-2), respectively. Time taken to reach maximum concentration in the anterior chamber for methanol, 1-propanol and 1-pentanol is 120+/-42, 160+/-26, and 260+/-26 min, respectively. The maximum concentration of methanol, 1-propanol and 1-pentanol achieved in the anterior chamber is 18.6+/-10.3, 9.4+/-3.2, and 5.9+/-1.3 microgml(-1)10(-4) respectively. Detectable 1-heptanol levels were not observed in the anterior chamber with the intravitreal dose administered. The shorter vitreal elimination half-lives of the alcohols studied suggest retina as major route of elimination from the vitreous body. The elimination rate constants of alcohols from the vitreous appear to be progressively decreasing with ascending chain length and lipophilicity (methanol to 1-heptanol). Among the alcohols studied, methanol produced the highest concentration in the anterior chamber following vitreal administration.