摘要:

Oral contraceptive steroids are of 2 types: oestrogens, of which ethinyloestradiol is the most important, and progestagens, of which levonorgestrel and norethisterone are the most commonly used. All these steroids can be measured by a number of analytical techniques but there is little doubt that radioimmunoassay is the most convenient. All the steroids are well absorbed in humans but while levonorgestrel is completely bioavailable, norethisterone has an average bioavailability of 70%. Ethinyloestradiol, too, is subject to presystemic metabolism with a mean bioavailability of 40 to 45%. The main site of presystemic metabolism is the gut wall, with the production of ethinyloestradiol sulphate. The progestagens norethynodrel, ethynodiol diacetate and lynoestrenol are quantitatively metabolised to norethisterone.The pharmacokinetics of the contraceptive steroids are best described by a 2-compartment open model. The terminal plasma half-life of levonorgestrel varies from 11 to 45 hours and of norethisterone from 5 to 14 hours. The &bgr;-phase half-life of ethinyloestradiol varies from 6 to 20 hours. The apparent volume of distribution of these contraceptive steroids (after intravenous administration) is between 1.5 and 4.3 L/kg. During long term treatment with oral contraceptive steroids, steady-state plasma concentrations of ethinyloestradiol (24 hours after administration) are between 10 and 200 pg/ml. Plasma concentrations of norethisterone and levonorgestrel at steady-state are higher than predicted from the single-dose kinetics because of enhanced binding of the progestagens following the induction of sex hormone binding globulin (SHBG) by ethinyloestradiol. Concentrations are in the range of 1.6 to 15.2 ng/ml for norethisterone and 0.8 to 4.5 ng/ml for levonorgestrel.All the contraceptive steroids are bound to proteins in plasma. Ethinyloestradiol is 97 to 98% bound to plasma albumin. The progestagens are bound both to albumin (levonorgestrel 93 to 95%; norethisterone 79 to 80%) and more specifically to SHBG. The binding capacity of SHBG can be enhanced by treatment with ethinyloestradiol or with more conventional enzyme-inducing drugs such as phenobarbitone, carbamazepine or rifampicin.Norethisterone and levonorgestrel are chiefly metabolised by reduction in the A ring and this is followed by conjugation with glucuronide or sulphate. The metabolism of levonorgestrel is stereoselective. Ethinyloestradiol is primarily hydroxylated at the 2 position but a wide variety of hydroxylated and methylated metabolites are formed and these are present both free and as glucuronide and sulphate conjugates. Ethinyloestradiol is conjugated directly at the 3 position (unlike the progestagens) and thus is liable to enterohepatic recirculation. Ethinyloestradiol sulphate concentrations in plasma are many times higher than that of the unchanged drug.The oral contraceptive steroids are involved in drug interactions of clinical significance. While the effect of contraceptive steroids on other drugs is small and unlikely to be of clinical significance, failure of contraception often occurs if enzyme-inducing agents such as rifampicin, phenobarbitone or carbamazepine are coadministered. Oral antibiotics do not seem to cause a significant loss of contraception in the large majority of women. Vitamin C will enhance the effect of contraceptive steroids by competing for sulphate conjugation in the gut wall, thus leading to increased bioavailability of ethinyloestradiol.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The administration of quinidine to patients receiving digoxin maintenance therapy results in a marked increase in the serum/plasma digoxin concentration. With over 90% of patients being affected the incidence of this drug interaction is rather high. The change in serum digoxin concentration is proportional to the dose of quinidine. At usual therapeutic doses of quinidine, the serum digoxin concentration tends to double on the average, although there is pronounced individual variation, the reported increase ranging from 25 to over 300%. The serum digoxin concentration begins to rise within 24 hours after starting quinidine and a new steady-state level is established in about 3 to 6 days. It remains elevated for as long as quinidine is co-administered. Quinidine increases the serum digoxin concentration in anuric patients also; in these patients it may take a week or more until a new steady-state is established.The sustained elevation of serum digoxin concentration during quinidine co-administration is undoubtedly due to a decrease in total body clearance of digoxin. Quinidine decreases both renal and extrarenal clearance of digoxin. Obviously quinidine interferes with renal tubular excretion of digoxin since it affects neither the glomerular filtration rate nor protein binding of digoxin. The mechanism by which quinidine decreases extrarenal clearance of digoxin remains to be elucidated.Conflicting results have been reported with regard to the influence of quinidine on the elimination half-life (t1/2) and volume of distribution of digoxin. At least in the relevant patient group, i.e. in cardiac patients on long term treatment with combined digoxin and quinidine, the digoxin t1/2is apparently increased, but both no change and a substantial decrease in volume of distribution during quinidine co-administration has been reported. Direct measurements of digoxin tissue levelsin vivoseem to favour the latter finding. However, specific binding of digoxinin vitrois unaffected by quinidine at concentrations thought to be in the therapeutic range. Whether quinidine interferes with nonspecific binding of digoxin remains to be determined.The clinical effect on the heart of the increased serum digoxin concentration in the quinidine-digoxin interaction is still controversial. However, the evidence available at present strongly suggests that the increase results at least partially in an increased cardiac effect. Likewise, data provided recently by the Boston Drug Surveillance Program and several case reports indicate an increased digoxin toxicity during quinidine administration. Based on our present knowledge of this drug interaction, only tentative therapeutic recommendations can be given.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The pharmacokinetics of different cardiac glycosides are altered by renal dysfunction in different ways, depending on their basic pharmacokinetic properties.Digoxin:The linearity of digoxin pharmacokinetics is unchanged by renal dysfunction, as is the bioavailability. Protein binding may be slightly reduced, but the change is of no clinical significance. The apparent volume of distribution is reduced by one-third to one-half, the change being roughly proportional to the degree of renal impairment. The significance of this change in terms of adjustment of the loading dose is controversial. I believe that the initial oral loading dose should be reduced from 15 &mgr;g/kg to 10 &mgr;g/kg in renal dysfunction, and supplemented only if there is evidence of a lack of response and no evidence of toxicity.The renal clearance of digoxin is reduced in renal dysfunction and becomes very closely related to the measured creatinine clearance at values of creatinine clearance below 30 ml/min. As a result, the renal elimination rate constant, and therefore the fraction of the total body load lost per day via the kidneys, falls in renal dysfunction. In contrast, the non-renal clearance of digoxin is probably unaffected. However, because of the fall in apparent volume of distribution the non-renal elimination rate constant rises slightly, accounting for the slight increase in faecally excreted digoxin in renal dysfunction. This rise in the non-renal fractional daily loss is not sufficient to counteract the fall in renal fractional daily loss and digoxin maintenance dosages at steady-state need to be reduced. For this purpose the creatinine clearance acts as an initial guide to the extent of the expected reduction in dose, but doses altered on this basis should be regarded as first approximations to the correct dose, and the dose subsequently readjusted according to the patient's clinical response, using the plasma digoxin concentration as a guide. It must be remembered, however, that because of technical problems with digoxin radioimmunoassay in renal dysfunction, and because of the difficulty in interpretation of the result, the plasma digoxin concentration in renal dysfunction is of less value than it is in normal renal function. The overall half-life of digoxin is prolonged in renal dysfunction and it therefore takes longer for a steady-state to be reached during maintenance dose therapy without a loading dose, and longer for toxicity, when it occurs, to resolve.Negligible amounts of digoxin are removed from the body by dialysis procedures. A transplanted kidney retains its ability to handle digoxin, and after transplantation the pharmacokinetics of digoxin return towards normal, depending on the overall improvement in renal function achieved.Digitoxin:There are technical problems with the measurement of digitoxin because of the need to separate digitoxin and its metabolites chromatographically before using the measurement techniques commonly applied. Such separation has not always been carried out, and this makes the interpretation of the available data more difficult.The bioavailability of digitoxin is unaffected by renal dysfunction. Protein binding is probably significantly reduced but the clinical significance of this effect is unclear since the apparent volume of distribution and total body clearance of digitoxin appear to be unchanged. In the nephrotic syndrome, which must be considered separately from the other forms of renal dysfunction, there is impaired protein binding but also probably loss of protein bound drug via the renal glomerulus. This leads to a proportionately large increase in total body and renal clearances, a shortening of the half-life and a fall in the steady-state plasma digitoxin concentrations. In other forms of renal dysfunction there is probably no change in half-life or in steady-state plasma digitoxin concentrations. There does seem to be a decrease in digitoxin renal clearance but this may be compensated for by increases in nonrenal clearance, both by non-renal excretion of unchanged digitoxin and by metabolic clearance, with increased formation of the active hydroxylated and hydrolysed metabolites, as well as of the relatively inactive reduced metabolites. Overall, the changes seem to contribute little of clinical importance. Little digitoxin is removed from the body by dialysis procedures.Lanatoside C, deslanoside, and the acylated digoxins:Since these glycosides are largely metabolised to digoxin, one would expect changes in their pharmacokinetics similar to those of digoxin. However, there is only enough information to conclude that this is probably so in the case of &bgr;-methyldigoxin. The protein binding of &bgr;-methyldigoxin is reduced, as is its apparent volume of distribution, and total body clearance. The reduction in total body clearance is mostly attributable to a reduction in renal clearance, which falls in parallel with creatinine clearance, although always remaining lower than creatinine clearance. Non-renal clearance falls little or not at all. As a result of these changes the overall half-life of &bgr;-methyldigoxin is prolonged and the fractional daily loss at steady-state is decreased. Dosages of &bgr;-methyldigoxin therefore need to be reduced in renal dysfunction. Little &bgr;-methyldigoxin is removed by haemodialysis.For &agr;-acetyldigoxin, renal clearance is reduced in proportion to renal function, and the half-life is prolonged. Little is removed by haemodialysis.Other glycosides:Little information is available about other cardiac glycosides. What little information there is, however, suggests that, as one would expect, the half-life is prolonged and renal clearance reduced for those glycosides which are mostly eliminated via the urine, while little or no change occurs for those glycosides which are mostly metabolised. Thus, for ouabain (g-strophanthin), and k-strophanthin, the half-life is prolonged and renal excretion decreased, while for proscillaridin, methylproscillaridin, and peruvoside there is no change. None of these glycosides is much affected by haemodialysis.Despite the changes in pharmacokinetics of digoxin compared with digitoxin, there is little to choose between the two drugs for use in patients with renal dysfunction. Arguments in favour of one or other can be marshalled but there is no good evidence that one is preferable to the other.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (±SD) peak plasma concentrations of dothiepin were 49 ± 27 &mgr;g/L at 3 ± 1.2h. Mean (± SD) estimates of other parameters were as follows: absorption half-life 1.1 ± 1.1h; distribution half-life 2.2 ± 0.8h; elimination half-life 25 ± 7h; apparent volume of distribution 70 ± 62 L/kg; and oral clearance 2.1 ± 1.6 L/kg/h.The mean (±SD) peak plasma concentration of dothiepin S-oxide was 125 ± 43 &mgr;g/L at 3.5 ± 1.3h with an elimination half-life of 22 ± 12h. The mean peak plasma concentration of northiaden was 6 ± 3 &mgr;g/L at 4.5 ± 1.1h, with an elimination half-life of 31 ± 12h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers.When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin.The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150mg nocte.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS