Chronic Dosing Studies Research Articles

Pharmacokinetics of voriconazole after oral and intravenous administration to horses

To characterize pharmacokinetics of voriconazole in horses after oral and IV administration and determine the in vitro physicochemical characteristics of the drug that may affect oral absorption and tissue distribution. 6 adult horses. Horses were administered voriconazole (1 mg/kg, IV, or 4 mg/kg, PO), and plasma concentrations were measured by use of high-performance liquid chromatography. In vitro plasma protein binding and the octanol:water partition coefficient were also assessed. Voriconazole was adequately absorbed after oral administration in horses, with a systemic bioavailability of 135.75 +/- 18.41%. The elimination half-life after a single orally administered dose was 13.11 +/- 2.85 hours, and the maximum plasma concentration was 2.43 +/- 0.4 microg/mL. Plasma protein binding was 31.68%, and the octanol:water partition coefficient was 64.69. No adverse reactions were detected during the study. Voriconazole has excellent absorption after oral administration and a long half-life in horses. On the basis of the results of this study, it was concluded that administration of voriconazole at a dosage of 4 mg/kg, PO, every 24 hours will attain plasma concentrations adequate for treatment of horses with fungal infections for which the fungi have a minimum inhibitory concentration <or= 1 microg/mL. Because of the possible nonlinearity of this drug as well as the potential for accumulation, chronic dosing studies and clinical trials are needed to determine the appropriate dosing regimen for voriconazole in horses.

Evaluation of the effects of photooxidized Echis carinatus venom on learning, memory and stress

Snake venoms are a mixture of complex proteins, which have many physical and pharmacological properties. Photochemical detoxification has been suggested to generate photooxidized Echis carinatus venom product (POECVP). Antigenically-active photooxidized species of Echis carinatus venom could be obtained by exposing the venom to ultraviolet radiation (UVR) in the presence of methylene blue. The aim of the present study was to evaluate the effects of POECVP on learning, memory and stress in rats. Detoxification of the photooxidized venom was evident since the POECVP-treated group had longer survival time than the group of mice treated with Echis carinatus venom product (ECVP) following intraperitoneal and intracerebral injections. Photooxidized Echis carinatus venom product showed antidepressant activity by prolonging sleep onset and shortening the duration of pentobarbitone-induced hypnosis in mice. In single and chronic dose studies with rats, we observed that POECVP significantly decreased the time needed to reach food in T-maze, shortened transfer latency in elevated plus-maze, and decreased immobility time in forced swim test. We concluded that although there is a possibility of employing POECVP in the treatment of depressive and chronic degenerative illnesses as a nonherbal and nonsynthetic alternative for patients not responding to the available therapy, further investigation is still needed.

Determining the Effects of Antiepileptic Drugs on Cognitive Function in Pediatric Patients With Epilepsy

The majority of children with epilepsy are of normal intelligence; however, a significant subset suffers from temporary or permanent cognitive impairment. Factors that affect cognitive function are myriad and include the neuropathology underlying the epilepsy, seizures, epileptiform activity, psychosocial problems, and antiepileptic drug side effects. Although cognitive impairment is often wrongly attributed to the effects of antiepileptic drugs, antiepileptic drugs do impair cognition in some children. Clinicians should be aware of the differential cognitive effects of antiepileptic drugs and should monitor cognitive function closely when adding or changing therapy. Based on published data from prospective, chronic dosing studies, phenobarbital and topiramate have the highest potential for causing cognitive dysfunction.

Differential influences of peroxisome proliferator-activated receptors gamma and -alpha on food intake and energy homeostasis.

Chronic treatment with compounds activating peroxisome proliferator-activated receptor (PPAR)gamma and -alpha influences body energy stores, but the underlying mechanisms are only partially known. In a chronic-dosing study, equiefficacious antihyperglycemic doses of the PPAR gamma agonist pioglitazone and PPAR alpha/gamma dual activator ragaglitazar were administered to obesity-prone male rats. The PPAR alpha agonist fenofibrate had no effect on insulin sensitivity. Pioglitazone transiently increased and fenofibrate transiently decreased food intake, whereas ragaglitazar had no impact on feeding. As a result, body adiposity increased in pioglitazone-treated rats and decreased in fenofibrate-treated rats. PPAR gamma compounds markedly increased feed efficiency, whereas PPAR alpha agonist treatment decreased feed efficiency. In fenofibrate-treated rats, plasma acetoacetate was significantly elevated. Plasma levels of this potentially anorectic ketone body were unaffected in pioglitazone- and ragaglitazar-treated rats. High-fat feeding markedly increased visceral fat pads, and this was prevented by pioglitazone and ragaglitazar treatment. Pioglitazone treatment enlarged subcutaneous adiposity in high-fat-fed rats. In conclusion, PPAR gamma activation increases both food intake and feed efficiency, resulting in net accumulation of subcutaneous body fat. The impact of PPAR gamma activation on feeding and feed efficiency appears to be partially independent because the PPAR alpha component of ragaglitazar completely counteracts the orexigenic actions of PPAR gamma activation without marked impact on feed efficiency.

Immunotoxicity of aflatoxin B1 in rats: effects on lymphocytes and the inflammatory response in a chronic intermittent dosing study.

We investigated the effects of aflatoxin B1 (AFB1) on isolated splenic lymphocytes and the histo-morphologic changes in the spleens and liver of Fisher-344 male rats. Weaned animals were fed chow diets that contained 0, 0.01, 0.04, 0.4, or 1.6 ppm AFB1, using an intermittent dosing regimen (4 weeks on and 4 weeks off AFB1), for 40 weeks. An additional group of animals was fed the 1.6 ppm AFB1 diet continuously. The intermittent dosing regimen was designed to evaluate effects of cumulative dose and exposure for risk assessment comparisons. The percentages of T and B cells were affected as shown by flow cytometric analysis after the dosing cycles. The observed changes appeared to reverse or compensate to some extent after the off cycles. Lymphocytes were stimulated in culture for analysis of the production of IL-2, IL-1, and IL-6. Significantly increased production of IL-1 and IL-6 was seen in the second dosing cycle (12 weeks) and the second "off" cycle (16 weeks) at the higher doses. Inflammatory infiltrates were seen in the liver after eight weeks of continuous and intermittent dosing and were increased in size and number at 12 weeks in both 1.6 ppm dose groups correlating with the peak production of Il-1 and IL-6. We concluded that AFB1 effects on the immune system can be either stimulatory or suppressive dependent on a critical exposure window of dose and time. Immune cells in spleen such as T-lymphocytes and macrophages, both important mediators of inflammatory responses to tissue damage, were affected differently in the continuous and intermittent exposures to AFB1.

Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma.

The type 2 helper T cell (T(H)2) cytokine interleukin (IL)-4 is thought to play a central role in the early stages of asthma. In an effort to develop an antibody treatment for asthma that neutralizes the effects of IL-4, a murine monoclonal antibody, 3B9, was generated with specificity for human IL-4. In vitro studies demonstrated that 3B9 inhibited IL-4-dependent events including IL-5 synthesis, (T(H)2) cell activation and up-regulation of immunoglobulin E expression. 3B9 was then humanized (pascolizumab, SB 240683) to reduce immunogenicity in humans. SB 240683 demonstrated species specificity for both monkey and human IL-4 with no reactivity to mouse, rat, cow, goat or horse IL-4. Pascolizumab inhibited the response of human and monkey T cells to monkey IL-4 and effectively neutralized IL-4 bioactivity when tested against several IL-4-responsive human cell lines. Affinity studies demonstrated rapid IL-4 binding by pascolizumab with a slow dissociation rate. In vivo pharmacokinetic and chronic safety testing in cynomolgus monkeys demonstrated that pascolizumab was well tolerated, and no adverse clinical responses occurred after up to 9 months of treatment. Three monkeys developed an anti-idiotypic response that resulted in rapid pascolizumab clearance. However, in the chronic dosing study the antibody response was transient and not associated with clinical events. In conclusion, pascolizumab is a humanized anti-IL-4 monoclonal antibody that can inhibit upstream and downstream events associated with asthma, including (T(H)2) cell activation and immunoglobulin E production. Clinical trials are under way to test the clinical efficacy of pascolizumab for asthma.

Salmeterol 100 μg: an analysis of its tolerability in single- and chronic-dose studies

A combination product containing fluticasone propionate 100 or 250 microg and salmeterol 50 microg has recently been made available in the United States. Some patients, if previously instructed to double their inhaled corticosteroids, may double this product, inadvertently receiving higher doses of salmeterol, potentially causing systemic beta2-agonist-related effects. To examine the systemic effects of single and chronic doses of salmeterol 100 microg. Forty-four studies including a salmeterol 100 microg treatment arm were identified. Data on predictable systemic effects were available in 10 single-dose and 9 chronic-dose studies lasting more than 7 days, in patients with asthma (6 adult, 2 pediatric) or chronic obstructive pulmonary disease (1 study), which were included in a weighted, pooled analysis. Single 100-microg dose studies: mean change from baseline in heart rate was +2.3 beats per minute and systolic blood pressure +0.4 mm Hg. Tremor and palpitations were reported in 5.7% and 2.8%. Other systemic effects included a decrease in serum potassium for 3 subjects (2.1%); an increase in serum glucose, 1 subject (0.7%); and electrocardiographic (ECG) events, 24 cases (17.0%). Twenty-three of these were from one crossover study which reported 27 ECG events after placebo. Chronic dose studies (salmeterol 100 microg): mean change in heart rate and systolic blood pressure were +1.8 beats per minute and -0.2 mm Hg. Tremor and palpitations were reported in 5.6% and 1.7% of 1,504 patients. Thirteen recorded a decrease in serum potassium (0.9%) and 5 an increase in serum glucose (0.3%). Nine patients had ECG events (0.6%). Eight of these were "arrhythmia" from one study, which also reported 12 events before treatment. The mean systemic effects of salmeterol 100 microg are small and of doubtful clinical relevance. Patients (and their caregivers) can be reassured that inadvertently taking double doses of the new combination product are unlikely to affect them adversely.

Hematological effects and metal residue concentrations following chronic dosing with tungsten-iron and tungsten-polymer shot in adult game-farm mallards.

The U.S. Fish and Wildlife Service required a chronic dosing study that assessed the health and reproductive effects of tungsten-iron and tungsten-polymer shot in adult game-farm mallards (Anas platyrhynchos) prior to granting permanent approval of the shot for waterfowl hunting. Herein, we present the effects of tungsten-iron and tungsten-polymer shot on various hematologic parameters and metal residue concentrations in the femur, liver, kidneys, and gonads. Thirty-two-bird groups (sexes equal) of adult mallards were dosed orally with eight #4 steel shot (control), eight #4 tungsten-iron shot, or eight #4 tungsten-polymer shot on days 0, 30, 60, 90, and 120 of a 150 day trial (26 January 1998 to 25 June 1998). An additional 12 mallards (sexes equal) received eight #4 lead shot (positive control) on day 0 of the study. Lead-dosed mallards had significantly decreased hematocrit, hemoglobin concentration, and whole-blood delta aminolevulinic acid dehydratase activity on day 7, as well as significant changes in a number of plasma chemistry parameters compared to ducks in the control, tungsten-iron, or tungsten-polymer groups. Mallards dosed with tungsten-iron or tungsten-polymer shot had occasional significant differences in hematocrit and plasma chemistry values when compared to control mallards over the 150 day period, but these changes were not considered to be indicative of deleterious effects. Low concentrations of tungsten were detected in gonad and kidney samples from males and females and in liver samples from females dosed with tungsten-polymer shot. Tungsten was also detected in femur samples from tungsten-polymer-dosed mallards. Higher concentrations of tungsten were detected in femur, liver, kidney, and gonad samples from tungsten-iron-dosed ducks. Tungsten-iron or tungsten-polymer shot repeatedly administered to adult mallards did not cause adverse hematological effects during the 150 day trial. Concentrations of tungsten in the femur, liver, kidneys, and gonads were generally higher in tungsten-iron-dosed ducks when compared to tungsten-polymer-dosed ducks.

GlutathioneS-Transferase-Mediated Mutagenicity of Trihalomethanes inSalmonella typhimurium:Contrasting Results with Bromodichloromethane and Chloroform

Trihalomethanes (THMs) are the most prevalent disinfection by-products identified in chlorinated drinking water. Among the THMs, chloroform (CHCl3) generally occurs at the highest concentration in finished water, but the concentrations of each of the brominated THMs (CHBrCl2, CHBr2Cl, and CHBr3) can exceed that of CHCl3. Each of these four THMs was carcinogenic in rodents in chronic oral dosing studies. This study assessed THM mutagenicity in a strain ofSalmonella typhimuriumTA1535 that was transfected with rat theta-class glutathioneS-transferase T1-1 (+GST). The +GST strain and its nontransfected parent strain (−GST) were employed in a plate-incorporation assay and exposed for 24 hr to the vapor of individual THMs at concentrations up to 25,600 ppm in sealed Tedlar bags. Base-substitution revertants were produced in the +GST strain in a dose-dependent fashion by CHBrCl2but not by CHCl3. At 4800 ppm CHBrCl2, which produced a calculated agar concentration of 0.67 mm, there were 419 ± 75 revertants per plate compared to a spontaneous level of 23 ± 5. CHCl3produced a doubling of revertants only at the two highest concentrations tested (19,200 and 25,600 ppm). These results indicate that bromination of THMs confers the capability for theta-class GST-mediated transformation to mutagenic intermediates at low substrate concentrations, suggesting the possibility of a similar activation route in humans. Further, the very low affinity of the GSH-dependent pathway for CHCl3demonstrates that different THMs can induce adverse effects via different mechanisms, indicating that risk evaluations of THMs should not treat members of this class as if they shared a common mode of action.

Primaquine Alters Antioxidant Enzyme Profiles in Rat Liver and Kidney

The effects of primaquine treatment on antioxidant enzyme activities were investigated in rat liver and kidney. Male Sprague-Dawley rats were treated with 0.21 mg/kg daily for two weeks (chronic treatment) or a single dose at 0.21 or 0.63 mg/kg. Antioxidant enzyme activities were determined in liver and kidney cytosolic fractions whereas glutathione (GSH) and malondialdehyde (MDA) levels were determined in tissue samples. Results for the liver showed increases in cytosolic superoxide dismutase (SOD) and glutathione peroxidase (GPX) enzymatic activities after chronic primaquine treatment. Levels of MDA, a marker for lipid peroxidation, were also increased by more than 50% indicating enhanced oxidative damage in the liver. In the single dose study, 0.63 mg/kg primaquine caused a more than 100% increase in liver SOD and a 36% increase in NAD (P) H: quinone oxidoreductase (NQOR) activities. Results for the kidney, however, showed fewer primaquine-induced changes in antioxidant enzyme activities when compared to the liver in both the chronic and single dose studies. Overall, our results indicate that primaquine treatment causes an oxidative stress in the two rat organs. These results are consistent with the known pro-oxidant effects of primaquine in vivo, and supplement current knowledge on the effects of antimalarial drugs on various enzyme systems.

Protocol design considerations that relate to demonstrating the safety and effectiveness of chemopreventive agents

As with other drugs, applications for marketing approval of new chemopreventive agents in the United States must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. Knowledge of a drug's pharmacologic actions and metabolism may benefit protocol design, by identifying the patient populations and dosing schedules associated with a favorable risk/benefit profile. With availability of appropriate preclinical data, including standard assessments of an agent's toxicology, effects on reproductive performance, and genotoxicity, initial Phase I studies of 1-3 months may be performed in normal volunteers or an appropriate higher risk population. For chronic dosing studies of longer duration, preclinical toxicology studies of longer duration are relevant. Enrollment in chemoprevention studies should be directed toward individuals at sufficient risk of developing cancer so that potential benefit may counterbalance the unpredictable and possibly serious adverse effects that may be observed with prolonged administration of a study drug. Phase I and II studies with clinical dosing lasting up to 12 months often afford opportunities to assess drug effect on surrogate endpoint biomarkers that may correlate with endpoints of clinical effectiveness. Phase III and late phase II chemopreventive investigations should routinely utilize a prospective, randomized study design (double-masked and placebo-controlled, when possible). To support marketing approval, there must be evidence that a chemopreventive agent significantly delays or prevents the occurrence of malignancy, with acceptable safety. In some circumstances, modulation of a surrogate marker may provide a basis for marketing approval, before more definitive endpoint data become available. However, the acceptability of a surrogate depends on the nature and quality of the data supporting its predictive value. Given the considerations of large study size, long duration, and high cost that may hamper development of potential agents, studies designed to examine the predictive value of surrogate endpoint biomarkers are of great importance to the future development of chemoprevention research.

Liposomal methylprednisolone in rats: dose-proportionality and chronic-dose pharmacokinetics/pharmacodynamics.

Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the immune system and enhances immunosuppressive activity of the steroid. We performed dose-dependent and chronic dose studies of L-MPL versus MPL. Male Lewis rats received 10 mg/kg i.v. bolus doses of L-MPL (Solu-Medrol). Plasma samples were obtained over an 8 day period and MPL concentrations were assayed by HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte proliferation induced with PHA. Drug concentrations declined in a similar manner over the first few hours following MPL or L-MPL. Free MPL was cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistence over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L-MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day 8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg i.v. doses of L-MPL versus MPL twice a week produce plasma drug profiles similar to those obtained after single doses, indicating that neither free nor liposomal steroid accumulates in tissues. Liposomes without drug simultaneously administered with MPL caused partial prolongation of plasma steroid half-life (8.4 hr). These studies clarify factors causing prolonged drug persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular pharmacokinetics, and secondary effects of the liposomes are complicating factors in use of L-MPL.

Antihypertensive and Cardiovascular Effects of a New Potassium Channel Opener, TCV-295, in Rats and Dogs

The antihypertensive and cardiovascular properties of a new potassium channel opener, TCV-295, were studied in rats and dogs. In conscious, spontaneously hypertensive rats (SHR), TCV-295 (0.03-1 mg/kg orally, p.o.) reduced blood pressure (BP) dose dependently with slow onset of action. The antihypertensive effects induced by TCV-295 lasted much longer than those of levcromakalim and nisoldipine, and the reflex tachycardia it evoked was less marked than that evoked by these drugs as compared at doses showing similar maximal hypotensive effects. Glibenclamide (30 mg/kg intravenously, i.v.) inhibited the TCV-295-induced BP decrease in anesthetized rats. In a 4-week chronic dosing study in SHR, TCV-295 (0.3 mg/kg/day p.o.) produced neither potentiation nor tolerance to its antihypertensive action and no rebound hypertension occurred when drug treatment was discontinued. In anesthetized normotensive dogs, TCV-295 (4.5 micrograms/kg/min i.v.) induced BP reductions accompanied by reductions in systemic vascular resistance. TCV-295 also reduced resistances of the coronary, vertebral, mesenteric, and renal vascular beds, and the most marked effect was observed in the coronary vasculature. Myocardial O2 consumption was reduced by TCV-295, possibly owing to afterload decrease. These results suggest that TCV-295 has a desirable profile for an antihypertensive agent.

A Double-Masked, Placebo-Controlled Evaluation of Timolol in a Gel Vehicle

We evaluated a topical formulation of timolol in an anionic heteropolysaccharide gellan gum (Gelrite). Fifty-five white patients with ocular hypertension entered a double-masked, placebo-controlled, four-period, incomplete block crossover study. After washout of any ocular hypotensive medications, the intraocular pressure of both eyes of all patients was measured at 0 (09:00 h), 2, 4, 6, 8, 12, and 24 h (diurnal baseline). Patients were then randomized to receive, at 2-week intervals, one drop of each of four of the six treatments in one eye (0.008% timolol gel, 0.1% timolol gel, placebo gel, 0.008% timolol solution, 0.1% timolol solution, and placebo solution). Fellow eyes received the appropriate placebo. As measured by least-squares means, adjusted for the unmedicated baseline diurnal values, there was a clear dose-response, with the 0.1% treatments being more effective ocular hypotensive agents than the 0.008% treatments, which in turn were more effective than the placebo treatments. Within each concentration at several observation points, the gel formulation elicited a 1-2-mm Hg greater efficacy than the solution. Gel-treated subjects had a greater incidence of blurred vision. We conclude that formulation of timolol with a gel may increase efficacy, and thus duration of action. This may possibly allow use of a lower concentration of timolol or a reduced frequency of instillation. Further evaluation in chronic dosing studies is justified.

An HPLC Method for the Determination of Diltiazem and Three of its Metabolites in Serum

Abstract A high performance liquid chromatographic method was developed for the determination of diltiazem and three of its metabolites in serum. Serum samples are extracted with methyl-tert.-butyl ether followed by back-extraction into 0.05N sulfuric acid. Doxepin hydrochloride was used as internal standard. A cyanopropylsilane column in the reverse-phase mode was utilized with a mobile phase of acetonitrile-phosphate buffer-triethylamine (pH 3.5). Using UV detection at 237nm, the lower limit of sensitivity was 1.5–3.0 ng/ml. Recovery and reproducibility results and possible interferences from other compounds are presented and discussed. The assay procedure was applied to a chronic oral dosing study in humans to assess the disposition of diltiazem and its primary metabolites.

Salicylate pharmacokinetics in patients with rheumatoid arthritis.

1. The pharmacokinetics of salicylic acid (SA) and its major metabolite salicyluric acid (SU) were studied in nine patients with rheumatoid arthritis following a 900 mg oral dose of acetylsalicylic acid and during 6 weeks of chronic administration of enteric coated aspirin (3,900 mg day). Response to therapy was also monitored. 2. The various pharmacokinetic parameters determined in the study were similar to those observed in other single dose salicylate studies amongst healthy volunteers but were not predictive of salicylate concentration in the chronic dose study. 3. Plasma concentrations of SA (total and unbound) were found to decline significantly over the 6 weeks and plasma SU concentrations increased. 4. During the chronic dosing study, there was a significant increase in the Vmax (total and unbound) for the formation of SU, whilst the Km and SU clearance remained constant. Also, the elimination rate constant (k) for salicylate was not significantly affected. 5. Therapeutic response to salicylate therapy was not significantly affected by the decline in SA concentrations.

The effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of metoprolol

The impact of cimetidine, ranitidine and placebo on the pharmacokinetics of metoprolol, given either as a single dose (100 mg) or for 7 days (100 mg b.d.), has been evaluated in two separate studies. The doses used were 800 mg cimetidine daily and 300 mg ranitidine daily. The subjects were all young, healthy volunteers. In the single dose study, cimetidine produced a marked increase in the peak plasma concentration of metoprolol and in the area under the plasma concentration-time curve; ranitidine had less effect, though the area under the curve was significantly greater than placebo. In the chronic dosing study, the area under the curve for metoprolol was also significantly higher on cimetidine (1796 ng h/ml; P less than 0.001) whereas the area under the curve on ranitidine (1258 ng h/ml) was comparable to that on placebo (1183 ng h/ml). Despite these drug-induced changes in plasma metoprolol concentration, neither cimetidine nor ranitidine altered the change in exercise-induced heart rate during dosing with metoprolol.

Pharmacokinetics of pholcodine in healthy volunteers: single and chronic dosing studies.

1. The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2. Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross-over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3. Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay. 4. After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 +/- 1.2 h) and eliminated slowly with a mean half-life of 50.1 +/- 4.1 h. The renal clearance of pholcodine was 137 +/- 34 ml min-1 and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 +/- 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5. After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6. Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration.

Aspects of the clinical pharmacology of nifedipine, a dihydropyridine calcium-entry antagonist.

Although nifedipine has been characterized in terms of its general vasodilatory effects, this dihydropyridine must still be regarded as investigational with regard to available pharmacokinetic and pharmacodynamic data. Although limited studies are available, it is clear that the pharmacokinetic and pharmacodynamic data reported are quite variable among subjects. Further, it appears that single dose elimination kinetics may be of little predictive value with regard to the kinetic characteristics present during chronic drug administration. It is also possible that the plasma level-effect correlations for the drug may differ with single and sustained dosing regimens. At the present time the lack of definitive data to define the relationships between plasma levels of nifedipine and associated drug effects suggests that measurement of drug levels in plasma serves primarily as a research tool and to identify patient noncompliance or abnormal absorption of the drug. Finally, since the prototype of this class, nifedipine, has been shown to have the potential for non-linear kinetics during chronic dosing, dihydropyridine analogs should be subject to extensive pharmacokinetic and pharmacologic evaluation during both single and chronic dosing studies, prior to widespread clinical use.

Effects of ranitidine on the disposition of metoprolol.

The effects of ranitidine on the pharmacokinetics of metoprolol were examined in two studies. In the first study, pharmacokinetics of single doses of metoprolol were examined in six subjects before, during and after ranitidine administration for 1 week. Peak concentrations of metoprolol were increased on ranitidine but its half-life and clearance were unaltered. In the second study, 12 subjects received metoprolol twice daily for 1 week; once with ranitidine and once with placebo. Ranitidine had no effects on the chronic-dose pharmacokinetics or pharmacodynamics of metoprolol. The chronic dose study suggests no inhibition of the metabolism of metoprolol by ranitidine. The single dose study suggests, however, that some interaction of an as yet unknown nature, cannot be excluded.