1 The influence of enzyme induction with antipyrine and pentobarbitone was studied on the rates of formation of the major metabolites of antipyrine: 4-hydroxyantipyrine, norantipyrine and 3-hydroxymethyl-antipyrine + 3-carboxy-antipyrine. The inducing drugs were given to panels of healthy volunteers for 8 days and prior to and after this period antipyrine total elimination clearance was determined in plasma, whereas the partial clearances for production of the individual metabolites were assessed on the basis of urinary excretion data. 2 Antipyrine total clearance had significantly increased by 16% following treatment with antipyrine, which could almost entirely be attributed to a selective increase in the rate of production of norantipyrine. 3 With pentobarbitone total clearance of antipyrine had increased by 60%, which was associated with a significant increase in the clearance of production of all three metabolites. However, the increase in norantipyrine formation was significantly higher than the increase in 4-hydroxyantipyrine and 3-hydroxymethyl-antipyrine formation. 4 The most likely explanation for these differences in the degree of induction of the different metabolic routes of antipyrine, is that different enzymes are involved in the different routes. Apparently the enzyme involved in norantipyrine formation is most sensitive to induction by antipyrine and pentobarbitone. By measuring rates of antipyrine metabolite formation it may be possible to study the degree of selectivity of enzyme inducers on oxidative drug metabolism.

1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and in females in either phase of the cycle. The elimination half-life was 27.3 + 1.3 h in males, 27.7 + 1.5 h in females in the follicular phase and 29.6 + 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 ± 2.7 ml/min, 58.2 + 3,3 and 55.8 ± 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 + 2.3 and 31.2 + 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 + 4.6 and 45.6 ± 4.1 ml/min) was significantly lower than in males (P < 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 ± 0.1%) to females in the luteal phase of the cycle (12.4 + 0.5%) to females using OC-steroids (13.5 ± 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (C; = 323 + 30 ml/min in females using OC-steroids, 530 + 37 ml/min in males and 459 + 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have higher steady state levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.

No abstract

The pharmacokinetics of antipyrine in plasma and saliva, and urinary excretion of its major metabolites, were studied following i.v. and oral administration of antipyrine 500 mg to 6 healthy volunteers. Data from both plasma and saliva showed that the oral bioavailability of antipyrine given as an aqueous solution was complete. The saliva/plasma concentration ratio was constant with time from about 3 h onwards, with a mean value of 0.87 after oral and 0.91 after i.v. administration. It is concluded that the pharmacokinetic parameters of antipyrine can be satisfactorily established on the basis of salivary data, although the volume of distribution and clearance values are then slightly too high. After i.v. administration, 3.8 +/- 1.9% of the dose was excreted in urine as unchanged antipyrine in 48 h, 24.9 +/- 6.3% as 4-hydroxyantipyrine, 16.5 +/- 3.2% as norantipyrine, 13.0 +/- 2.2% as 3-hydroxymethyl-antipyrine and 5.8 +/- 1.0% as 3-carboxy-antipyrine. No significant differences were observed following oral administration. The half-lives calculated from the linear part of the urinary excretion rate curves of the metabolites were about the same for oral and i.v. administration, and were of the same order of magnitude as the elimination half-life of parent drug in plasma and saliva. It is important for determination of the ultimate metabolite ratio that urine is collected for at least 36 h, because there is a delay in the excretion of 3-hydroxymethyl-antipyrine in urine.

No abstract