Plasma Concentrations Of Doxycycline Research Articles

The effect of doxycycline on canine neutrophil functions

Doxycycline is a broad-spectrum tetracycline-class antibiotic that is frequently used to treat bacterial infections. Its use has also been described in immune-mediated diseases due to its immunomodulatory properties. The aim of this study was to evaluate the immunomodulatory effect of doxycycline on canine neutrophil functions. Therefore, the release of reactive oxygen species (ROS) and the formation of neutrophil extracellular traps (NETs) were determined after incubation of canine PMNs with doxycycline in three different concentrations (4 µg/mL, 20 µg/mL and 200 µg/mL) for one and three hours, respectively. Additionally, a neutrophil killing assay with a doxycycline-resistant Staphylococcus aureus was performed to determine the bactericidal effect of doxycycline treated PMNs in presence of plasma. Doxycycline significantly diminished the production of ROS. However, doxycycline concentrations of 4 µg/mL and 20 µg/mL significantly induced NETs. A synergistic bacteriostatic effect of PMNs and doxycycline on a doxycycline-resistant Staphylococcus aureus isolate was detectable. However, already PMNs and especially doxycycline alone inhibited the growth. In summary, doxycycline showed a concentration-dependent immunomodulatory property in canine PMNs with a reduced ROS production and increased NET-induction. This immunomodulatory effect resulted in a slightly increased elimination of a doxycycline-resistant Staphylococcus aureus by the doxycycline plasma concentrations achieved in dogs.

Doxycycline hyclate in late-term pregnant mares: pharmacokinetics, diffusion to the fetoplacental unit and safety in the resulting foal

Doxycycline is a second-generation tetracycline with excellent tissue penetration, high-protein-binding, and 5-10-fold higher lipophilic character than tetracycline. It is used to treat difficult-to-identify and atypical pathogens in diseases such as granulocytic anaplasmosis, Potomac fever, Lyme disease, and placentitis caused by Leptospira and nocardioform Actinomycetes. Despite routine use of doxycycline in pregnant mares, there is no data on their pharmacokinetics during pregnancy, transplacental diffusion, or potential toxicity to the fetus and resulting foal. This study aimed to determine the pharmacokinetics of doxycycline in the late-pregnant mare, its diffusion to the fetoplacental unit and its safety in the neonate. The study hypothesizes that doxycycline crosses the equine fetoplacental unit after administration during late-term pregnancy and is safe for the resulting foal. In experiment 1, six mares received a dose of compounded doxycycline hyclate (10mg/kg, p.o.) at 300d of gestation. Doxycycline plasma concentrations were measured with LC-MS/MS at 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 48h after administration to confirm absorption and pharmacokinetics. The compounded doxycycline used herein was absorbed rapidly, and maximum plasma concentrations were achieved in 0.79h. Pharmacokinetic parameters of the doxycycline were similar to previous studies using commercial canine preparations. In experiment 2, transplacental diffusion and safety to the resulting foal were studied after administration of repeated doses ofdoxycycline to late-term pregnant mares. Seven mares received doxycycline (10mg/kg p.o. q12h) from 320d of gestation until foaling, and six gestationally-age-matched mares served as controls. Once impending signs of imminent parturition were detected coupled with mammary gland secretion pH ≤6.4, foaling was induced with oxytocin (10-units, intramuscularly) to ensure a controlled sampling of fetal fluids. Fetal fluids and foal synovial fluids were harvested at foaling to determine doxycycline concentrations with LC-MS/MS. After parturition, foals had daily clinical examinations, blood chemistry, and complete blood cell counts performed for seven days. Shapiro-Wilk was used to test normal distribution and data were analyzed with ANOVA and Tukey's as post hoc. Mares received doxycycline on average for 15±2d (range 9-23d). No adverse side effects were associated with doxycycline treatment, and complete blood cell count or blood chemistry pre- and post-partum remained within normal reference ranges. Gestation length for doxycycline-treated mares (335±2d) was similar to controls (339±4) (P=0.4). Concentrations of doxycycline were 9-fold higher in the allantoic fluid (73.5±13.9ng/mL) than amniotic fluid (8.3±3.3ng/mL) and 1.5-fold higher in the foal's plasma (35.5±4.3ng/mL than its synovial fluid (23.6±4.3ng/mL). In conclusion, doxycycline was well-absorbed and detectable in fetal fluids, foal plasma, and synovial fluid, and no adverse effects were observed in mares nor their foals.

Doxycycline serum protein binding in pigs reveals a relatively high free fraction.

Doxycycline is an antibiotic widely used in pig farming. As with all antibiotics, only the free concentrations are considered to be bacteriologically active. Historically, the free fraction (fu) in pig plasma has been estimated at 7%, which, given the effective dosage regime used in pigs, leads to free plasma concentrations of doxycycline largely lower than the minimum inhibitory concentrations of the target pathogens. This apparent inconsistency led us to reassess plasma protein binding of doxycycline in pigs. Using an equilibrium dialysis method, the extent of doxycycline binding was measured individually in 26 pigs for total doxycycline concentration ranging from 10 to 1000 μmol/L. Analysis of the data using a non-linear mixed-effects model demonstrated linearity of plasma protein binding with a mean fu value of 31% and a relatively low inter-subject variability of approximately 10%. This new data showing that the free fraction is four times greater than what could have been anticipated from historical data is discussed in particular for the calculation of the PK/PD cut-offs, which are used to establish the clinical breakpoints for antimicrobial susceptibility testing.

Pharmacokinetic Profile of Doxycycline in Koala Plasma after Weekly Subcutaneous Injections for the Treatment of Chlamydiosis.

Simple SummaryDoxycycline is an antimicrobial used for treating chlamydial infections in various species, including the koala. The dose and route of administration used initially are based on first principles. Therefore, this study investigates the absorption, distribution, metabolism, and excretion of subcutaneous doxycycline injections, and evaluates the suitability of the current dosage regimen for inhibiting chlamydial pathogens. The results suggest that the current doxycycline dosage remained therapeutically effective for up to six days after each dose, with some accumulation over successive doses. All koalas in the study improved clinically and tested negative for chlamydial pathogens post-treatment before being released. This study contributes to determining the optimal dosage of doxycycline to treat chlamydiosis safely and effectively in infected koalas.Six mature, male koalas (Phascolarctos cinereus), with clinical signs of chlamydiosis, were administered doxycycline as a 5 mg/kg subcutaneous injection, once a week for four weeks. Blood was collected at standardised time points (T = 0 to 672 h) to quantify the plasma doxycycline concentrations through high-pressure liquid chromatography (HPLC). In five koalas, the doxycycline plasma concentration over the first 48 h appeared to have two distinct elimination gradients; therefore, a two-compartmental analysis was undertaken to describe the pharmacokinetic (PK) profile. The average ± SD maximum plasma concentration (Cmax) was 312.30 ± 107.74 ng/mL, while the average time ± SD taken to reach the maximum plasma concentration (Tmax) was 1.68 ± 1.49 h. The mean ± SD half-life of the distribution phase (T1/2 α) and the elimination phase (T1/2 β) were 10.51 ± 7.15 h and 82.93 ± 37.76 h, respectively. The average ± SD percentage of doxycycline binding to koala plasma protein was 83.65 ± 4.03% at three different concentrations, with a mean unbound fraction (fu) of 0.16. Using probability of target attainment modelling, doxycycline plasma concentrations were likely to inhibit 90% of pathogens with the doxycycline minimum inhibitory concentration (MIC) of 8.0–31.0 ng/mL, and the reported doxycycline MIC to inhibit Chlamydia pecorum isolates at the area under the curve/minimum inhibitory concentration (AUC/MIC) target of ≥24. All koalas were confirmed to be negative for Chlamydia pecorum using loop-mediated isothermal amplification (LAMP), from ocular and penile urethra swabs, three weeks after the last doxycycline injection.

Effects of Single and Repeated Doses on Disposition and Kinetics of Doxycycline Hyclate in Goats.

Simple SummaryDoxycycline is used to treat bacterial infections such as pneumonia, skin and soft tissue infections, urinary tract infections, salmonellosis, and colibacillosis in goats. In goats, the single intravenous and intramuscular pharmacokinetics of doxycycline are known. However, there is no information regarding oral pharmacokinetics. This study aims to determine the single and repeated pharmacokinetics, bioavailability, and accumulation of doxycycline hyclate. Although doxycycline hyclate exhibited low intramuscular and oral bioavailability, its oral administration with favorable properties such as weak accumulation, wide distribution volume and long elimination half-life can be useful in the treatment of infections caused by susceptible pathogens in goats.The aims of this study in goats were to determine the pharmacokinetics of doxycycline hyclate following single intravenous (IV), intramuscular (IM) and oral administrations of 20 mg/kg and to evaluate the pharmacokinetics and accumulation of doxycycline hyclate after repeated oral administrations at a 20 mg/kg dose every 24 h for 5 days. Six healthy male goats were used for the study. The study was performed in four periods according to a longitudinal study with a 15-day washout period. Plasma concentrations of doxycycline were determined using HPLC-UV and analyzed by a non-compartmental method. IM injection of doxycycline caused swelling and pain due to irritation in the injection site. After IM and oral administrations, terminal elimination half-life (t1/2λz) and mean residence time (MRT) were prolonged and areas under the curve (AUCs) were low. The mean bioavailability of IM and oral administration was 51.51% and 31.39%, respectively. Following repeated oral administration, the accumulation ratio of doxycycline was 1.76. Pharmacokinetic properties including weak accumulation, wide distribution volume and long elimination half-life can make doxycycline hyclate valuable for repeated use via an oral route in the treatment of some infectious diseases in goats. However, the determination of pharmacodynamic effects on susceptible pathogens isolated from goats is also necessary to confirm the drug dosage regimen.

Subantimicrobial Dose Doxycycline Worsens Chronic Arthritis-Induced Bone Microarchitectural Alterations in a Mouse Model: Role of Matrix Metalloproteinases?

Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease hallmarked by irreversible damage of cartilage and bone. Matrix metalloproteinases (MMPs) involved in connective tissue remodeling play an important role in this process. Numerous MMPs have been examined in humans and animals, but their functions are still not fully understood. Therefore, we investigated the role of MMPs in the K/BxN serum-transfer model of RA with the broad-spectrum MMP inhibitor subantimicrobial dose doxycycline (SDD) using complex in vivo and in vitro methodolgy.Methods: Chronic arthritis was induced by repetitive i.p. injections of K/BxN serum in C57BL/6J mice. SDD was administered daily in acidified drinking water (0.5 mg/mL, 80 mg/kg) during the 30 days experimental period. Mechanonociceptive threshold of the paw was evaluated by aesthesiometry, grasping ability by grid test, arthritis severity by scoring, neutrophil myeloperoxidase activity by luminescence, vascular hyperpermeability and MMP activity by fluorescence in vivo imaging and the latter also by gelatin zymography, bone structure by micro-computed tomography (micro-CT). Plasma concentrations of doxycycline were determined by liquid chromatography-mass spectrometry analysis.Results: K/BxN serum induced significant inflammatory signs, mechanical hyperalgesia, joint function impairment, increased myeloperoxidase activity and vascular hyperpermeability. Significant increase of MMP activity was also observed both in vivo and ex vivo with elevation of the 57–60, 75, and 92 kDa gelatinolytic isoforms in the arthritic ankle joints, but neither MMP activity nor any above described functional parameters were influenced by SDD. Most importantly, SDD significantly reduced bone mineral density in the distal tibia and enhanced the Euler number in the ankle. Arthritis-induced microarchitectural alterations demonstrating increased irregularity and cancellous bone remodeling, such as increased Euler number was significantly elevated by SDD in both regions.Conclusion: We showed increase of various MMP activities in the joints by in vivo fluorescence imaging together with ex vivo zymography, and investigated their functional significance using the broad-spectrum MMP inhibitor SDD in the translational RA model. This is the first demonstration that SDD worsens arthritis-induced bone microarchitectural alterations, but it appears to be independent of MMP inhibition.

Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.

The effect of sucralfate tablets vs. suspension on oral doxycycline absorption in dogs.

The purpose of this study was to determine the effect of concurrent sucralfate (tablet or suspension) on doxycycline pharmacokinetics and to determine the effects of delaying sucralfate by 2h on doxycycline absorption. Five dogs were included in a crossover study receiving: doxycycline alone; doxycycline concurrently with sucralfate tablet; doxycycline followed 2h by sucralfate tablet; doxycycline concurrently with sucralfate suspension; and doxycycline followed 2h by sucralfate suspension. Doxycycline plasma concentrations were evaluated with liquid chromatography with mass spectrometry. No interaction was seen when sucralfate was administered as a tablet. Sucralfate tablet fragments were frequently observed in some dogs' feces. The area under the curve (AUC) and maximum plasma concentration (CMAX ) were significantly lower (P<0.001) in the concurrent sucralfate suspension group (AUC 7.2h·μg/mL, CMAX 0.43μg/mL) than with doxycycline alone (AUC 36.0h·μg/mL, CMAX 2.53μg/mL) resulting in a relative bioavailability of 20%. Delaying sucralfate suspension by 2h after doxycycline administration resulted in no difference in doxycycline absorption as compared with doxycycline administration alone with a relative bioavailability of 74%. The lack of an interaction with sucralfate tablets suggests sucralfate should be administered as a suspension rather than tablet in dogs.

Population pharmacokinetics of doxycycline in the tears and plasma of northern elephant seals (Mirounga angustirostris) following oral drug administration

To assess tear and plasma concentrations of doxycycline following oral administration to northern elephant seals (Mirounga angustirostris). Pharmacokinetic study. 18 juvenile northern elephant seals without signs of ocular disease. Study seals were receiving no medications other than a multivitamin and were free from signs of ocular disease as assessed by an ophthalmic examination. Doxycycline (10 or 20 mg/kg [4.5 or 9.1 mg/lb]) was administered orally every 24 hours for 4 days. Tear and plasma samples were collected at fixed time points, and doxycycline concentration was assessed by means of liquid chromatography-tandem mass spectrometry. Concentration-time data were calculated via noncompartmental analysis. Following administration of doxycycline (10 mg/kg/d, PO), maximum plasma doxycycline concentration was 2.2 μg/mL at 6.1 hours on day 1 and was 1.5 μg/mL at 4.0 hours on day 4. Administration of doxycycline (20 mg/kg/d, PO) produced a maximum plasma doxycycline concentration of 2.4 μg/mL at 2.3 hours on day 1 and 1.9 μg/mL at 5.8 hours on day 4. Doxycycline elimination half-life on day 4 in animals receiving doxycycline at a dosage of 10 or 20 mg/kg/d was 6.7 or 5.6 hours, respectively. Mean plasma-to-tear doxycycline concentration ratios over all days were not significantly different between the low-dose (9.85) and high-dose (9.83) groups. For both groups, doxycycline was detectable in tears for at least 6 days following cessation of dosing. Oral administration of doxycycline at the doses tested in the present study resulted in concentrations in the plasma and tears of northern elephant seals likely to be clinically effective for treatment of selected cases of systemic infectious disease, bacterial ulcerative keratitis, and ocular surface inflammation. This route of administration should be considered for treatment of corneal disease in northern elephant seals and possibly other related pinniped species.

Assessment of Plasma Concentrations and Potential Adverse Effects of Doxycycline in Cockatiels (Nymphicus hollandicus) Fed a Medicated Pelleted Diet

Doxycycline hyclate was mixed with soybean oil and then added to a low-fat pelleted diet that contained approximately 2.4% fat, which produced a final diet that contained a calculated 6.4% fat and 300 mg doxycycline per kilogram of diet. The medicated diet was fed to 9 healthy adult cockatiels (Nymphicus hollandicus) for 47 days; a control group of 6 birds received the identical diet without doxycycline. Trough doxycycline plasma concentrations were measured 7 times during treatment and ranged from 0.98 to 3.83 microg/mL with an overall median of 2.09 microg/ mL. The birds were observed daily, weighed, and examined at least weekly, and selected plasma biochemical parameters were measured before treatment and at days 21 and 42. No adverse effects were noted, except one treatment bird became obese. This medicated diet may be suitable for treating spiral bacteria and Chlamydophila psittaci infections in cockatiels that will consume a pelleted diet.

Ecological impact of doxycycline at low dose on normal oropharyngeal and intestinal microflora

This study included 34 healthy volunteers (16 male and 18 female) aged 19–37 years, of whom 17 received doxycycline 40mg capsules orally once daily (o.d.) and 17 received placebo 40mg capsules orally o.d. for 16 weeks. Plasma, saliva and faecal samples were collected before drug administration and at 4, 8, 16 and 20 weeks. Plasma samples were assayed for doxycycline concentrations, and saliva and faecal samples were investigated for doxycycline concentrations and microbiological analyses. Plasma concentrations of doxycycline in the doxycycline group were as follows: baseline visit (2h), 0.20–0.61mg/L; 4-week visit, 0.30–1.04mg/L; 8-week visit, 0.43–1.49mg/L; 16-week visit, 0.32–1.12mg/L; and 20-week visit 0mg/L. No doxycycline was detected in plasma in the placebo group. No doxycycline concentrations in the saliva samples were found in the doxycycline or placebo groups at the five visits. Faecal concentrations of doxycycline in the doxycycline group were as follows: baseline visit, 0mg/kg; 4-week visit, 0–3.71mg/kg; 8-week visit, 0–1.85mg/kg; 16-week visit, 0–4.10mg/kg; and 20-week visit, 0mg/kg. No doxycycline faecal concentrations were detected in the placebo group. Minor effects on the aerobic and anaerobic oropharyngeal microflora were observed both in the doxycycline and placebo groups. There were minor changes in the number of enterococci and Escherichia coli in the doxycycline and placebo groups. The anaerobic intestinal microflora in the doxycycline and placebo groups was not changed, and no Clostridium difficile strains were isolated.

Pharmacokinetic behavior of doxycycline after intramuscular injection in sheep

To determine the pharmacokinetics of a commercial formulation of doxycycline hyclate after IM administration of a single dose to sheep. 11 healthy domestic sheep. For each sheep, doxycycline was administered as a single dose of 20 mg/kg, IM. Blood samples were obtained prior to and for 84 hours after doxycycline administration. Plasma concentrations of doxycycline were determined via high-performance liquid chromatography with UV detection. Pharmacokinetic data were analyzed with noncompartmental methods. Mean ± SD values for pharmacokinetic parameters included maximum plasma concentration (2.792 ± 0.791 μg/mL), time to reach maximum plasma concentration (0.856 ± 0.472 hours), mean residence time (91.1 ± 40.78 hours), elimination half-life (77.88 ± 28.45 hours), and area under the curve (65.67 ± 9.877 μg•h/mL). Results indicated that doxycycline had prolonged absorption and elimination in sheep after IM administration. A daily dose of 20 mg/kg would be sufficient to reach effective plasma concentrations against Chlamydia spp (minimum inhibitory concentration, 0.008 to 0.031 μg/mL) and Staphylococcus aureus (minimum inhibitory concentration, 0.12 μg/mL). Doxycycline administered IM could be an option for therapeutic use in sheep, although further studies are needed.

Influence of Mycotoxins and a Mycotoxin Adsorbing Agent on the Oral Bioavailability of Commonly Used Antibiotics in Pigs

It is recognized that mycotoxins can cause a variety of adverse health effects in animals, including altered gastrointestinal barrier function. It is the aim of the present study to determine whether mycotoxin-contaminated diets can alter the oral bioavailability of the antibiotics doxycycline and paromomycin in pigs, and whether a mycotoxin adsorbing agent included into diets interacts with those antibiotics. Experiments were conducted with pigs utilizing diets that contained blank feed, mycotoxin-contaminated feed (T-2 toxin or deoxynivalenol), mycotoxin-contaminated feed supplemented with a glucomannan mycotoxin binder, or blank feed supplemented with mycotoxin binder. Diets with T-2 toxin and binder or deoxynivalenol and binder induced increased plasma concentrations of doxycycline administered as single bolus in pigs compared to diets containing blank feed. These results suggest that complex interactions may occur between mycotoxins, mycotoxin binders, and antibiotics which could alter antibiotic bioavailability. This could have consequences for animal toxicity, withdrawal time for oral antibiotics, or public health.

Pharmacokinetics and Bioequivalence Study of Doxycycline Capsules in Healthy Male Subjects

The aim of the present study was to compare the bioavailability of doxycycline (CAS 564-25-0) from two different doxycycline hyclate (CAS 24390-14-5) capsules (Monodoks 100 mg capsule as test preparation and 100 mg capsule of the originator product as reference preparation) in 24 healthy male subjects. The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 16 days. Blood samples for pharmacokinetic profiling were taken up to 72 h post-dose, and doxycycline plasma concentrations were determined with a validated HPLC method with UV-detection. Maximum plasma concentrations (Cmax) of 1,715.1 ng/ml (test) and 1,613.3 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 28,586.5 ng x h/ml (test) and 29,047.5 ng x h/ml (reference) were calculated. The median tmax was 1.88 h (test) and 2.00 h (reference). Plasma elimination half-lives (t1/2) of 16.49 h (test) and 16.75 h (reference) were determined. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA) and the 92.39 %-103.53% (AUC(0-infinity)) and 98.45%-111.74% (Cmax). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and Cmax the 90% confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80 0%-125%.

Orally administered doxycycline accumulates in synovial fluid compared to plasma

Tetracycline compounds have been used to slow the progression of osteoarthritis (OA) and rheumatoid arthritis but the concentration of doxycycline attained in synovial fluid following oral, low-dose administration has yet to be determined. To determine the concentration of doxycycline in synovial fluid following oral, low-dose administration. Six mature horses received doxycycline (5 mg/kg bwt q. 12 h for 5 doses). Venous blood and synovial fluid samples were collected at t=0, 0.25, 0.5, 1, 12, 24, 48 and 72 h. Doxycycline concentrations were measured using reverse phase high pressure liquid chromatography with ultraviolet detection. Doxycycline concentrations at all time points after t=0 were above the lower limit of quantification for the assay. Plasma concentrations of doxycycline were above 0.21 microg/ml at t=0.5 h. The mean+/-s.d. peak concentration (Cmax) of doxycycline in plasma was 0.37+/-0.22 microg/ml and time to peak concentration was 0.54+/-0.19 h. Synovial fluid concentrations of doxycycline were above 0.12 microg/ml 1 h after drug administration. The mean Cmax of doxycycline in the synovial fluid was 0.27+/-0.10 microg/ml. The penetration factor of doxycycline from plasma into synovial fluid, as determined by a ratio of the area-under-the-curve for synovial fluid:plasma during the sampling period, was 4.6. Orally administered doxycycline distributes easily into synovial fluid with a penetration factor of 4.6. Terminal half-life of the drug in synovial fluid was longer than in the plasma, indicating possible accumulation in this compartment. Further in vivo studies are warranted to define a medication protocol prior to routine clinical use of doxycycline for the treatment of OA.

Interindividual variability in plasma concentrations after systemic exposure of swine to dietary doxycycline supplied with and without paracetamol: A population pharmacokinetic approach1

Anorexigenic substances released during infection may hinder the therapeutic efficacy of in-feed antibiotics. Paracetamol (acetaminophen; PARA) inhibits the anorexia of infection and seems to improve the clinical efficacy of doxycycline (DOX) against bacterial respiratory disease in swine herds. In order to verify whether PARA selectively stimulates intake of DOX-medicated feed in diseased pigs, we documented the pharmacokinetics (PK) of DOX when coadministered with PARA and examined the effect of in-feed PARA on the interindividual variability in plasma concentrations after systemic exposure to in-feed DOX in swine herds with respiratory disease. Systemic exposure to DOX was measured with the area under the curve (AUC) of its plasma concentrations over time. First, a rich-sampling PK study of in-feed and i.v. DOX (10 mg/kg of BW) and PARA (30 and 10 mg/kg of BW, respectively) was performed on 5 pigs. The PK profiles of in-feed DOX were used in mathematical simulations to determine 5 optimal sampling times for the farm-based population PK study. A randomized, blind, parallel PK study was performed in 2 herds with bacterial respiratory disease, where liquid feed was fortified with DOX alone (5 mg x kg of BW(-1) x meal(-1)) or combined with PARA (15 mg x kg of BW(-1) x meal(-1)). Medicated meals were given twice, 12 h apart, to group-housed growing pigs (n > 50 pigs x treatment(-1) x herd(-1), totaling 215 pigs). Plasma concentrations of DOX and PARA were measured with HPLC. At variance with our expectations, PARA decreased (P = 0.069) mean AUC of in-feed DOX and did not decrease its variability (P > 0.34). Mean AUC of DOX increased with feed intake and with initial exposure to DOX, and was greater in sick animals. Therefore, symptomatic PARA-induced improvement in bacterial respiratory disease control with DOX is more likely caused by its analgesic/antipyretic effects than by its orexigenic effect. Interindividual variation in the AUC of DOX was large in pigs given group medication, even when sufficient feeding space was allowed and the amount of feed offered was greater than their requirements. Therefore, future studies to improve the efficacy of group antibiotic therapy should focus on feeding behavior characteristics as well as biopharmaceutical properties of medicated feeds.

Disposition kinetics of doxycycline in chickens naturally infected with Mycoplasma gallisepticum

1. The pharmacokinetic properties of doxycycline were determined in healthy chickens and chickens naturally infected with Mycoplasma gallisepticum after a single intravenous (i.v.) and oral administration of the drug at 20 mg/kg body weight. Tissue residues of the tested drug after an oral dose of 20 mg/kg given twice daily for 5 consecutive days were also estimated in diseased chickens. 2. The plasma concentrations of doxycycline following single i.v. and oral administration were higher in healthy chickens than in diseased ones. Following i.v. injection, the elimination half-life (t 1/2β), distribution half-life and mean residence time (MRT) were longer in healthy chickens than in diseased birds. The values of total body clearance (Cl B) and volume of distribution (V dss) were larger in healthy chickens than in diseased birds. 3. After single oral administration, the absorption half-life (t 1/2ab) and the elimination half-life were longer in normal birds than in diseased ones. The maximum plasma concentration of the drug was higher in normal chickens than in diseased ones. 4. Following repeated oral administration, the concentration of doxycycline in all tissues except muscle was higher than the corresponding concentrations in plasma. Concentrations of doxycycline in different tissues were in the following order: kidney > liver > lung > muscle. The drug was detected in liver and kidney in substantial concentrations on d 5 post administration of the last dose whereas, on d 7, its concentration in all tissues was below the lower limit of the sensitivity of the assay method used. Because of the low sensitivity of the microbiological assay method used in this study, a safe withdrawal time for doxycycline in diseased birds could not be estimated for the meanwhile.

Comparative bioavailability study of doxycycline hyclate (equivalent to 100 mg doxycycline) capsules (doxycin vs vibramycin) for bioequivalence evaluation in healthy adult volunteers

This investigation was carried out to evaluate the bioavailability of a new capsule formulation of doxycycline (100 mg), doxycin, relative to the reference product, vibramycin (100 mg) capsules. The bioavailability was carried out in 24 healthy male volunteers who received a single dose (100 mg) of the test (A) and the reference (B) products after an overnight fast of at least 10 hours on 2 treatment days. The treatment periods were separated by a 2-week washout period. A randomized, balanced 2-way cross-over design was used. After dosing, serial blood samples were collected for a period of 48 hours. Plasma concentrations of doxycycline were analyzed by a sensitive and validated high-performance liquid chromatography assay. The pharmacokinetic parameters for doxycycline were determined using standard noncompartmental methods. The parameters AUC(0-t), AUC(0-infinity), Cmax, K(el), t(1/2) and Cmax/AUC(0-infinity) were analyzed statistically using log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pharmacokinetic parameters: AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were within the range 80-125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis of the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were 95.98-109.56%, 92.21 to 107.66%, 93.90-112.56%, and 96.0 to 106.91% respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) by the Schuirmann's two 1-sided t-tests. Therefore, the 2 formulations were considered to be bioequivalent.

Assessment of plasma concentrations of doxycycline in budgerigars fed medicated seed or water

To determine whether plasma doxycycline concentrations considered effective for treatment of avian chlamydiosis could be safely established and maintained in budgerigars via administration of doxycycline in water or seed. Prospective study. 68 healthy mature budgerigars. In 14-day trials, plasma doxycycline concentrations were measured in budgerigars provided with water containing 0, 50, 100, 200, or 400 mg of doxycycline hyclate/L or a hulled seed diet containing 0, 100, 200, or 400 mg of doxycycline hyclate/kg. On the basis of these results, birds were fed seed containing 300 mg of doxycycline/kg for 42 days, and a control group received unmedicated seed. Blood samples for plasma doxycycline analysis were collected either in the morning on treatment days 4, 7 14, 21, 28, 35, and 42 or in the afternoon on days 12, 26, and 40. Birds were observed daily. On days 14, 28, and 42, physical and plasma biochemical variables, PCV, and total solids concentration were measured; cloacal specimens were obtained for bacteriologic and fungal culture. During a 14-day period, treatment with water containing < or = 400 mg of doxycycline/L did not maintain plasma doxycycline concentrations of > or = 1 microg/mL, but seed containing 300 mg of doxycycline hyclate/kg maintained mean plasma doxycycline concentrations > 0.98 microg/mL for 42 days without notable adverse effects. Results suggest that hulled seed containing 300 mg of doxycycline hyclate/kg can safely establish and maintain plasma doxycycline concentrations that are considered adequate for treatment of chlamydiosis in adult nonbreeding budgerigars.

Plasma Concentrations of Doxycycline in Selected Psittacine Birds When Administered in Water for Potential Treatment of Chlamydophila psittaci Infection

Infection by Chlamydophila psittaci (formerly Chlamydia psittaci) is a common cause of morbidity and mortality in companion psittacine birds and is transmissible to humans. Replication of Chlamydophila is inhibited by plasma doxycycline concentrations greater than 1 μg/ml, but prolonged treatment periods of 30–45 days are needed to eliminate infection. Medication of birds for this prolonged period is difficult with current treatment methods. In this study, drinking water medicated with doxycycline hyclate at 800 mg/L was provided ad libitum to healthy African grey parrots (Psittacus erithacus timneh) and Goffin's cockatoos (Cacatua goffini) for 42 days. Blood samples for doxycycline analysis were collected on treatment days 4, 7, 14, 21, 28, 35, and 42. Mean doxycycline concentrations exceeded 1 μg/ml throughout the 42-day treatment period. In the African grey parrots, the mean doxycycline concentration (± SD) for all plasma samples collected during the study was 1.51 ± 0.68 μg/ml and doxycycline concentrations were greater than 1 μg/ml in 73% of the samples. In the Goffin's cockatoos, the overall mean was 2.78 ± 1.00 μg/ml and doxycycline concentrations exceeded 1 μg/ml in all samples. No adverse effects were noted in the African grey parrots. All of the 8 treated Goffin's cockatoos were physically healthy, but changes in plasma biochemical analyses suggested mild hepatic damage in 3 birds. Results of plasma biochemical analyses in these cockatoos were within reference ranges when retested 7 days after doxycycline treatment ended. The results of this study suggest that doxycycline-medicated water can safely maintain plasma concentrations adequate for treating avian Chlamydophila infections in African grey parrots and Goffin's cockatoos housed under standardized conditions.