Polymorphisms of drug-metabolizing enzymes and risk of childhood acute lymphoblastic leukemia.

The involvement of phase I and II enzymes is well documented in the metabolism of a wide range of drugs and xenobiotics. Single-nucleotide polymorphisms (SNPs) of these enzymes are also known to alter their protein expression and function. Moreover, genetic susceptibility and environmental exposure have been proposed to be an etiology of cancer. We hypothesized that polymorphisms of these enzymes might affect the risk of childhood acute lymphoblastic leukemia (ALL). CYP 1A1, CYP 3A4*1B, CYP 3A5*3, CYP 3A5*6, GSTM1, and GSTT1 polymorphisms were genotyped by using PCR-RFLP in 107 children with ALL and 320 healthy controls. Allele and genotype frequencies of each of the SNPs were compared between two groups. It was found that the allele frequencies of CYP 1A1*1, *2A, *2B, and *4 were not different between cases and controls. CYP 3A4*1B allele frequency was only 0.8% and 0.9% in ALL and controls, respectively. CYP 3A5*1/*1, *1/*3, and *3/*3 genotype frequencies showed no statistically significant difference between patients and controls. CYP 3A5*6 was not detected in our population. The GSTM1 null genotype was significantly increased in children with ALL (OR 1.7; 95% CI, 1.0, 2.7). In contrast, the GSTT1 null genotype did not show this effect. Our data thus demonstrate that the GSTM1 null genotype might increase the risk of childhood ALL in a Thai population.

A pharmacogenetic study of trimethylaminuria in Orientals.

A study of the metabolism of trimethylamine was carried out in 103 healthy Thai volunteers (70 men and 33 women) and it was found that under normal dietary conditions 84-100% of trimethylamine was excreted in the urine in its N-oxide form. Five propositi living in different parts of the country were identified as having deficiency in the N-oxidation of this tertiary amine, because they excreted only 8-35% of this chemical as trimethylamine N-oxide. This metabolic defect was also confirmed by the results of an oral trimethylamine (600 mg) challenge experiment in which all five propositi were found to excrete an even smaller percentage of trimethylamine as trimethylamine N-oxide in their urine. The results of a study of the families of the two proband individuals, as well as those members of their preceding generations under normal dietary conditions, are consistent with the view that the disorder or metabolic defect is inherited in a Mendelian fashion as an autosomal recessive trait, similar to that reported for white Caucasian subjects.

Effect of caffeine on the bioavailability and pharmacokinetics of aspirin.

The objective of this study was to determine the influence of caffeine on aspirin bioavailability and pharmacokinetics in man. Two lots of the drugs were compared. The first lot (Lot # 1), which was caffeine-free, contained 650 mg aspirin plus 60 mg citric acid, whereas the second lot (Lot # 2) was caffeine-aspirin combination (650 mg aspirin plus 120 mg caffeine citrate, equivalent to 60 mg anhydrous caffeine). On two different occasions (2 weeks apart), the subjects received these two lots of drugs orally, i.e., each volunteer was given 650 mg aspirin (Lot # 1) or 650 mg aspirin plus 120 mg caffeine citrate (Lot # 2). It was found that caffeine significantly increased the rate of appearance as well as the maximum concentration of the salicylate in plasma by about 31 and 15 per cent, respectively. The area under the plasma concentration-time curve (AUC0 affinity) of salicylate was statistically higher in the subjects given the drug combination as compared to those given aspirin alone. Other pharmacokinetic parameters of the salicylate remained unchanged. It was therefore concluded that caffeine can increase the bioavailability of aspirin in man without any other effects on the salicylate disposition.

Biphasic effect of methadone on hepatic drug metabolism.

When methadone HCl (30 mg/kg, po) was given acutely to mice, it was found to inhibit drug metabolism as evidenced by a prolongation of hexobarbital sleeping time and zoxazolamine paralysis time. Pharmacokinetic studies revealed that this acute dose of the narcotic analgesic could also prolong the plasma half-life of aminopyrine without any change in its volume of distribution. When added to the incubation mixture containing 10,000 g mouse liver supernatant fraction and a complete system for measuring aminopyrine N-demethylase or aniline hydroxylase, methadone showed a dose-dependent inhibition of the enzymes; the former enzyme was inhibited to a greater extent than the latter one. However, subacute treatment of mice with methadone HCl (30 mg/kg, po, twice daily for 3 days) resulted in increases in liver weight, microsomal protein, and cytochrome P-450 content in consonant with the increased activities of four hepatic drug-metabolizing enzymes: aminopyrine N-demethylase, aniline hydroxylase, p-nitroanisole, O-demethylase, and benzphetamine N-demethylase. Moreover, both hexobarbital sleeping time and zoxazolamine paralysis time were shortened. The plasma half-life of aminopyrine was decreased. These changes were prevented by simultaneous administration of puromycin diHCl (80 mg/kg, ip). Methadone thus seems to act in a manner very similar to that of propoxyphene or SKF-525A, acting as a potent inhibitor of hepatic drug metabolism when given acutely and as an inducer when given subacutely.

Influence of caffeine on aspirin pharmacokinetics.

The effects of caffeine on the pharmacokinetics and bioavailability of aspirin were studied in 12 healthy adult male volunteers. The subjects received 650 mg of aspirin or 650 mg of aspirin with 120 mg of caffeine citrate orally. It was found that caffeine significantly increased the rate of appearance as well as the maximum concentration of salicylate in the plasma by about 25% and 17%, respectively. Moreover, area under the plasma concentration-time curve of salicylate was significantly higher in the subjects given the drug combination as compared to those given aspirin alone. There was no change in the plasma half-life, volume of distribution and clearance of salicylate.

Mechanism of inhibition of gastric acid secretion by hypertonic solutions and vasopressin.

An experiment was performed in female rats in order to assess the influence and mechanism underlying the effects of hyperglycemia, hypertonic saline and vasopressin upon the gastric acid secretion and mucosal blood flow (MBF). Infusion of isotonic saline did not alter acid output and gastric clearance of plasma aminopyrine whereas hypertonic solutions (20% glucose or 3% NaCl) significantly increased plasma osmolality and decreased the acid secretion within 30 min and recovered to normal levels after 2 h. Vasopressin also effectively inhibited acid secretion. Both hypertonic solutions and vasopressin decreased the mucosal blood flow. However, the ratio (R) of MBF to gastric secretory rate which is a helpful guide to the mechanism of secretory inhibition did not significantly change in either case. We concluded that all three agents probably had a direct action on secretion rather than decreasing MBF. The mechanism of inhabition of acid secretion and its relationship to MBF was suggested and discussed.