A method for calculating the mean absorption time of drugs undergoing reversible and first-pass metabolism

A method has been derived for calculating the mean absorption time of an oral drug and its interconversion metabolite which is generated from the drug systemically and presystemically. The method evolves from the convolution integral and requires plasma AUC and AUMC values after separate intravenous administration of the drug and its interconversion metabolite and oral administration of the drug. It can also be used to calculate the mean input time of a drug undergoing reversible metabolism and administered by any other extravascular route. Results of a simulation study using both errorless and errant data indicate that, when the absorption rate constant of a drug or its interconversion metabolite is not much larger than the apparent elimination rate constant, the proposed method performs satisfactorily. However, when the absorption rate constant of a drug or its interconversion metabolite is much larger than the apparent elimination rate constant, the proposed method appears to be inaccurate.     

Heterocyclic amines: evaluation of their role in diet associated human cancer

1 Heterocyclic amines are formed in parts per billion levels when meat is cooked.
2 The heterocyclic amines MeIQx and PhIP are efficiently absorbed into the systemic circulation after ingestion of cooked food.
3 We have shown that MeIQx and PhIP, both in vitro and in vivo , are substrates for human hepatic CYP1A2, which exclusively and efficiently catalyses their conversion to genotoxic hydroxylamines.
4 MeIQx and PhIP are promutagens. MeIQx is a very powerful bacterial mutagen whereas PhIP is a more potent mammalian cell mutagen. Using a mammalian cell target gene, hprt , we have shown that PhIP induces a characteristic mutational 'fingerprint'.
5 MeIQx and PhIP are carcinogenic in bioassays. The PhIP mutational 'fingerprint' has been detected in the Apc gene of 5/8 colonic tumours induced by PhIP in rats.     

Population toxicokinetics of tetrachloroethylene

 In assessing the distribution and metabolism of toxic compounds in the body, measurements are not always feasible for ethical or technical reasons. Computer modeling offers a reasonable alternative, but the variability and complexity of biological systems pose unique challenges in model building and adjustment. Recent tools from population pharmacokinetics, Bayesian statistical inference, and physiological modeling can be brought together to solve these problems. As an example, we modeled the distribution and metabolism of tetrachloroethylene (PERC) in humans. We derive statistical distributions for the parameters of a physiological model of PERC, on the basis of data from Monster et al. (1979). The model adequately fits both prior physiological information and experimental data. An estimate of the relationship between PERC exposure and fraction metabolized is obtained. Our median population estimate for the fraction of inhaled tetrachloroethylene that is metabolized, at exposure levels exceeding current occupational standards, is 1.5% [95% confidence interval (0.52%, 4.1%)]. At levels approaching ambient inhalation exposure (0.001 ppm), the median estimate of the fraction metabolized is much higher, at 36% [95% confidence interval (15%, 58%)]. This disproportionality should be taken into account when deriving safe exposure limits for tetrachloroethylene and deserves to be verified by further experiments. Received: 20 April 1995/Accepted: 24 August 1995     

Can bone metabolism markers be adopted as an alternative to scintigraphic imaging in monitoring bone metastases from breast cancer?

Bone scintigraphy plays a major role in the diagnosis of bone metastases. The clinical utility of new biochemical markers of bone metabolism has recently been investigated in various bone diseases. This study evaluated the role of some bone metabolism markers in comparison with bone scan in the follow-up of breast cancer patients. We studied 149 patients with breast cancer, 33 (22%) of whom had bone metastases. IRMAs were used for the evaluation of blood levels of osteocalcin, bone alkaline phosphatase (BAP), the C-terminal propeptide of type I procollagen and the C-terminal cross-linked telopeptide of type I collagen (ICTP). Multivariate regression analysis showed that menopausal status (P=0.007) and metastatic bone lesions (P=0.001) affected bone marker levels. When considering post-menopausal women, the only subset in which bone metabolism marker behaviour could be reliably investigated, we found a high degree of overlap in marker distribution for scan-positive and scan-negative patients. Discrimination between scan-negative and scan-positive patients based on the above markers, taken singly or jointly, was assessed by means of logistic discriminant analysis. The best discrimination was achieved with BAP, closely followed by ICTP. BAP and ICTP together gave a slight improvement over the use of the two markers separately. However, even in this case the degree of discrimination was poor and its clinical utility was limited. In fact, to achieve a specificity of 95%, the sensitivity of the test was about 20%; conversely, with a sensitivity of 95%, the specificity was below 10%. In conclusion, based on our findings, we believe that blood levels of the investigated markers cannot replace bone scintigraphy in the follow-up of breast cancer patients for the early detection of bone metastases. Received 14 April and in revised form 5 July 1997     

早期肠道营养对烧伤后肠源性高代谢的影响

从８０年代末起，通过对６００只大（豚）鼠、６０只兔和６０头小香猪所建立的４种烧伤后早期营养的动物模型，以及２１例严重烧伤病人对比分析，发现烧伤后早期肠道喂养可改善胃肠道血流供应，减轻肠道缺血再灌流损伤；可维护肠粘膜结构以及吸收、分泌、运动功能，降低门脉、中心静脉血内毒素水平，减少肠道内毒素易位；可降低伤后枯否细胞获得数、吞噬墨汁枯否细胞数和面积，以及其培养上清中肿瘤坏死因子（ＴＮＦ）量，对伤后枯否细胞的活化有刺激作用；可降低血胰高糖素、皮质醇、儿茶酚胺、ＴＮＦ、ＩＬ－８前列腺素Ｅ２（ＰＧＥ２）等递质的水平，降低高代谢，使烧伤４５％成人静息能量消耗（ＲＥＥ）在烧伤后４、８、１４ｄ的均值降低２８．６％。通过相关分析发现ＲＥＥ与血丙二醛（ＭＤＡ）、内毒素、分解激素、ＴＮＦ均呈显著正相关（ｒ＝０．７３８６～０．９９２２，Ｐ＜０．０５～０．０１）。     

Effect of prior exercise in Pi/PC ratio and intracellular pH during a standardized exercise. A study on human muscle using [31P]NMR

Seven subjects underwent a standard localized exercise of calf muscles in order to investigate whether the metabolic exercise-induced steady-state, as revealed by the evaluation of inorganic phosphate/phosphocreatine ratio, depends on the conditioning of the muscle just prior to the exercise. The experimental protocols consisted of two separate experiments using first [³¹P]nuclear magnetic resonance spectroscopy and second (on 3 subjects) infrared oxyphotometry to respectively follow variation of energy metabolism and tissular deoxygenation. The exercise consisted of 240 successive plantar flexions (0.5 Hz frequency) against a high load equivalent to SO% of the maximal voluntary contraction. This exercise was accomplished before cold exercise and after warm exercise, a warming-up period bringing to approximately 50% of Vo_2max. The results showed that: (1) steady-state level of phosphate/phosphocreatine and intracellular acidosis was significantly lowered by warming-up; (2) cold and warm exercise steady-state of calculated adenosine diphosphate values were not significantly different; (3) cold exercise rapidly induced a high tissular deoxygenation that is not observed during warm exercise; and (4) time-constant of phosphocreatine resynthesis is lowered after warm exercise but the initial slope of time-evolution is not modified. Parallel experiments also showed that phosphate/phosphocreatine steady-state was not modified in comparison with warm exercise when the same power of exercise was reached by stepwise incrementation of the charge. From these results we postulate that a better tissue oxygenation due to a global or localized warming-up allows to reach the same mechanical performance with a lower decrease of PCr content, owing to a faster adjustment of oxidative metabolism during the transitional period. However the aerobic pathway flux during the steady-state is probably the same before and after the warming-up despite different values of phosphate/phosphocreatine. As a consequence it can be assumed that this ratio is not a good indicator of the rate of muscle oxidative metabolism during the steady-state phase of the exercise.     

PET in cardiology: current status and clinical expectations

Summary. The development of positron emission tomography (PET) in the clinical environment along with the synthesis of biologically active molecules and tracer kinetic principles has provided a diagnostic tool for in vivo tissue characterization in humans. Moreover, based on the growing knowledge of cellular function on the molecular level of diseases PET biological imaging has stimulated the synthesis of numerous metabolic compounds labelled with the four primary positron-emitting radioisotopes C-ll, F-18, N-13 and 0–15. While the concept of biological imaging has gained attraction for probing both the central nervous system and neoplastic tissues, current diagnostic benefit from PET is probably best defined in cardiovascular medicine.     

乳酸脱氢酶实验检测细胞新陈代谢的实验研究

目的 探索LDH实验检测细胞活力的可行性。方法 原代培养骨髓细胞和软骨细胞，用LDH实验测定上述两组细胞的活力，并与镜下活体观察到细胞的生长状况相比较。与目前比较成熟的测定细胞活力的MTS实验的测得的值相比较。结果 LDH实验对上述两组细胞的活力的测定结果与镜下活体观察到的结果相符合。与MTS实验的测得的结果经统计学处理无显著差异。结论 LDH实验可用于细胞活力的直接测定，而对活细胞的生存、繁殖无影响。     

α<Subscript>2β</Subscript> adrenoreceptor 301–303 deletion polymorphism in polycystic ovary syndrome

α_2β adrenoreceptor 301–303 deletion polymorphism does not influence basal metabolic rate, insulin resistance or weight gain in Greek women with polycystic ovary syndrome.