Antipyrine and doxycycline pharmacokinetics in patients with thyroid disorders.
Pathological conditions are known to affect pharmacokinetics of many drugs. Antipyrine half-life is used as a marker of liver microsomal enzyme function. Antipyrine pharmacokinetics, therefore, was investigated in 23 thyrotoxic and 11 euthyroid goitre patients. Of these, 11 thyrotoxic and 9 euthyroid goitre patients also participated in doxycycline bioavailability studies. In thyrotoxic patients, antipyrine half-life and AUCo infinity and doxycycline Cpmax and AUCo infinity were found to be reduced as compared to those of healthy euthyroid normal subjects. Following treatment of thyrotoxicosis, the antipyrine half-life and AUCo infinity returned to normal. Doxycycline AUCo infinity returned to near normal range but Cpmax did not.
Thyroid hormones play an important role in regulating various metabolic processes. Subjects with hyperthyroidism have increased basal metabolic rate and hyper-dynamic circulation status. It is possible therefore that the pharmacokinetics of drugs may be altered by the thyroid status. The pharmacokinetics of anti-pyrine ,,,, and paracetamol were observed to be altered in both hyper-and hypothyroidism. However, no such alterations in the metabolism of diazepam or phenytoin were noted in hyperthyroid patients.
Doxycycline, a scmisynthetic tetracycline, is commonly used to treat various infections, due to its advantages of almost complete absorption (90-95%), long half-life, broad spectrum of activity and higher urinary concentrations, yielding good results in the therapy of urinary tract infections?
The present study was designed to investigate the pharmacokinetics of doxycycline in patients with various thyroid disorders. Antipyrine pharmacokinetics were also investigated in these subjects for comparison.
Newly detected 23 thyro-toxic (8 males and 15 females), and 11 euthyrold goitre (2 males and 9 females) patients in the age group of 19-50 years participated in the antipyrine pharmacokinetic studies. Of the above series, 12 thyro-toxic (5 males and 7 females) and 9 euthyroid goitrous patients (1 male and 8 females), participated in the doxycycline pharmacokinetic study. Diagnosis of thyrotoxicosis was established on the basis of detailed clinical examination and thyroid radioiodine uptake, T3 charcoal uptake and the plasma concentration of protein bound radioiodine, Twenty-five (12 males and 13 females) euthyroid, normal, healthy volunteers of similar age and sex as that of patients were included in the antipyrine kinetics study. Eleven (3 males and 8 females) of these also participated in the doxycycline pharmacokinctics study.
Patients with evidence of any diseases of heart, liver or kidney, with any infection, and/or treated with any drug upto one month prior to the study were excluded. Routine liver function tests, kindney function tests, complete blood count and serum cholesterol were carried out both in patients and in the normal volunteers. The study was approved by the local Ethical Committee. Written informed consent was obtained from all subjects.
Anti-pyrine was administered orally in the dose of 18 mg/kg body weight after overnight fasting and the subjects continued fasting for 3 more hours after administration of anti-pyrine. Five ml of saliva was collected before and 3, 5, 7, 9, 11, 13 and 24 hours after administration of anti-pyrine, The subjects were asked to rinse their mouth 3-4 times with water before each collection of saliva samples. The anti-pyrine determination was carried out by the spectrophotometric method of Brodic et al  as modified in our laboratory by Desai et al (Sensitivity 5 ?g/ ml-1 and recovery from saliva: 96.5%).
Antipyrine half-life (t ½) and area under the curve (AUCo¥) were calculated by standard methods.
The thyro-toxic patients were then treated with carbimazote or radioactive iodine. Of the 17 thyro-toxic patients, 4 received radioactive iodine, while 13 were treated with anti-thyroid drugs. They were followed up in the Endocrinology Clinic. An anti-pyrine test was repeated in 17 thyro-toxic patients after 6 months of therapy and/or when the patient was clinically euthyroid,
Of the above series 12 thyro-toxic and 9 euthyroid goitrous patients participated in the doxycycline pharmacokineties studies. On the 8th day after anti-pyrine test, doxycycline hydrochloride was administered orally as powder with 200 ml of water, in a single dose of 3 mg/kg body weight. Venous blood samples were obtained at 0, 0.5, 1.5, 2, 4, 6, 8, 24 and 30 hours after administration of doxycycline. The blood samples were centrifuged immediately to separate plasma. The plasma doxycyclinc levels were estimated by the method of Kohn . (Sensitivity 0.01 ?g/ml-1, recovery from plasma: 98.6%). Doxycycline half-life (t ½), K-absorption (Ka), peak plasma concentration (Cpmax), time to peak plasma concentration (t-max), and AUCo¥ were calculated by Standard methods.
The results were compared using ANOVA and paired t-test.
The half-life and AUCo¥ of antipyrine were observed to be significantly lower (p < 0.01 and p < 0.05 respectively) in thyrotoxic patients as compared to normal healthy volunteers [Table - 1]. Euthyroid goitrous patients did not show a deviation in the levels of these parameters in comparison to those of normal.
Doxycycline half-life in various thyroid disorders was similar as those in healthy normal subjects, however, the peak plasma concentration (Cpmax) and AUo? were lower in thyrotoxic patients though the difference was not significant.
Six months after therapy or when the thyrotoxic patients became euthyroid, antipyrine half-life and AUCo¥ returned near to the values obtained in healthy volunteers. Doxycycline AUCo¥ after treatment, also returned near to normal values, but the Cpmax values remained low.
Thyroid dysfunction is known to affect oxidation of those drugs that are metabolised by the mixed function oxidase. Hyperthyroidism exhibits an accelerating effect, whereas hypothyrodism results in reduced enzyme activity,.
Shortened antipyrine half-life as observed in our study suggests that the hepatic mixed unction oxidase is increased in thyrotoxicosis. Doxycycline half-life was not found to be significantly different in thyrotoxic patients. Hansen et a1 and Sherifield have also reported that metabolism of phenytoin and oral anticoagulants is not altered in thyrotoxicosis. Thus, different hepatic enzymes appear to be affected to different extents.
In our study, it was observed that the doxycycline Cpmax was lower in thyrotoxic patients, which could be attributed to an increase in the apparent volume of the central compartment in thyrotoxicosis. Doxycycline AUCo¥ was found to be lower in thyrotoxic patients. In thyrotoxicosis' increased liver blood flow has been reported. Doxycycline however, does not undergo marked first pass metabolism and therefore the observed low Cpmax and AUC values in thyrotoxicosis could not be attributed to the alteration in first pass effects. Doxycycline is 90-95% protein bound. In thyrotoxicosis, a decreased binding of drugs to albumin and alpha-1 acidglycoproteins has been reported. Thus, the increased amount of circulating free drug, increased renal blood flow and increased glomerular filtration rate, in thyrotoxic patients could have resulted in low Cpmax and lower AUCo¥ of doxycycline in our patients.
On treatment, while AUCo¥ values returned to normal, Cpmax values did not. This might suggest that the loading dose of doxycycline needs to be modified, in order to achieve therapeutic efficacy in patients with thyroid disorders, although the maintenance dose could be kept unchanged. However, further studies need to be carried out to confirm this aspect.