Pharmacokinetics of Anthelmintics
After administration, anthelmintics are usually absorbed into the bloodstream and transported to different parts of the body, including the liver, where they may be metabolized and eventually excreted in the feces and urine. The disposition of anthelmintics throughout the body is considerably more complex than can be described by a set of pharmacokinetic parameters in the peripheral circulation. Improved drug performance requires knowledge of drug behavior in the multicompartmental system, including the complex interaction between formulation and route of administration, physicochemical properties of the compound, and physiology of the compartment into which the drug is distributed.
Although many helminth parasites reside in the lumen or close to the mucosa, others live at sites such as the liver and lungs; for action against these, absorption of drug from the GI tract, injection site, or skin is essential. Intestinal parasites come in contact not only with the unabsorbed drug passing through the GI tract but also with the absorbed fraction in the blood as they feed on the intestinal mucosa, and with any that is recycled into the gut. This is an important aspect of efficacy of many of the benzimidazoles.
The pharmacokinetics of an anthelmintic, its rate of metabolism and excretion, and its safety profile determine the length of the withdrawal time; this period can vary among species and can also be affected by route of administration and dose. The usual site of metabolism of anthelmintics is the liver, where oxidation and cleavage reactions commonly occur.
With a few exceptions, eg, albendazole, oxfendazole, and triclabendazole, only limited amounts of any of the benzimidazoles are absorbed from the GI tract of the host. The limited absorption is probably related to the poor water solubility of these drugs. The little absorption that occurs is generally rapid, 2–7 hr after dosing with flubendazole and 6–30 hr after dosing with albendazole, fenbendazole, and oxfendazole, depending on the species. Many of the benzimidazoles and their metabolites re-enter the GI tract by passive diffusion, but the biliary route is the most important pathway for secretion and recycling of benzimidazoles in the GI tract.
A number of benzimidazoles (eg, febantel, thiophanate, netobimin) exist in the form of prodrugs that must be metabolized in the body to the biologically active benzimidazole carbamate nucleus. Febantel is hydrolyzed to the active metabolite fenbendazole, and netobimin undergoes processes of reduction, cyclization, and oxidation to yield albendazole sulfoxide. Benzimidazole sulfoxides such as oxfendazole and albendazole sulfoxide bind poorly to parasite β-tubulin and probably act as prodrugs for fenbendazole and albendazole, respectively. The thiometabolites have high affinity for helminth tubulin.
Metabolism of the benzimidazoles is variable and may alter their activity; eg, albendazole is rapidly and reversibly oxidized to its sulfoxide form. The sulfoxide may be irreversibly oxidized to its sulfone, which is significantly less active than the sulfoxide. Similarly, fenbendazole and oxfendazole (fenbendazole sulfoxide) are interchangeable, but the oxidation product fenbendazole sulfone is less active and is not reduced back to the sulfoxide or thio metabolites.
In ruminants, the benzimidazoles are most effective if deposited into the rumen. Administration directly into the abomasum, via the esophageal groove, may shorten the duration for drug absorption and increase the rate of excretion in the feces, which may reduce efficacy. For example, immediate arrival of oxfendazole in the abomasum after dosing reduces its efficacy from 91% to 45% against thiabendazole-resistant strains of Haemonchus contortus. The rumen acts as a drug reservoir from which plasma concentrations can be sustained, slowing the passage of unabsorbed drug through the GI tract.
The absorption and excretion of levamisole is rapid and not affected by the route of administration or ruminal bypass, because it is highly soluble. In cattle, blood concentrations of levamisole peak <1 hr after SC administration. These concentrations decline rapidly; 90% of the total dose is excreted in 24 hr, largely in the urine.
Pyrantel tartrate (or citrate) is well absorbed by pigs and dogs, less well by ruminants. The pamoate salt (synonym embonate) of pyrantel is poorly soluble in water; this offers the advantage of reduced absorption from the gut and allows the drug to reach and be effective against parasites in the large intestine, which makes it useful in horses and dogs. Metabolism of pyrantel is rapid, and the metabolites are excreted rapidly in the urine (40% of the dose in dogs); some unchanged drug is excreted in the feces (principally in ruminants). Blood concentrations usually peak 4–6 hr after PO administration.
Morantel is the methyl ester analogue of pyrantel and, in ruminants, it tends to be safer and more effective than pyrantel. It is absorbed rapidly from the upper small intestine of sheep and metabolized rapidly in the liver; ~17% of the initial dose is excreted in the urine as metabolites within 96 hr after dosing.
Macrocyclic lactones are hydrophobic, an important characteristic of this class of anthelmintics. Regardless of their route of administration, macrocyclic lactones are distributed throughout the body and some concentrate in adipose tissue. Liver tissue contains the highest residue for the longest, reflecting the route of elimination. Although the magnitude of lipophilicity differs among chemical types, the limited vascularization and slow turnover rate of body fat and the slow rate of release or exchange of drug from these lipid reserves can prolong the residence of drug in the peripheral plasma. Ivermectin is arguably the least lipophilic macrocyclic lactone, with the possible exception of eprinomectin. Moxidectin is ~100 times more lipophilic than ivermectin. Doramectin is less lipophilic than moxidectin but more than ivermectin or eprinomectin.
Ivermectin was the first commercially available macrocyclic lactone and has been the most extensively studied. When given IV, ivermectin has an elimination half-life of 32–178 hr, depending on species. Despite the higher dose rate of the injectable formulation in pigs (300 mcg/kg) compared with that of cattle (200 mcg/kg), the maximum concentration (Cmax) and area under the curve (AUC) in peripheral plasma in pigs are about one-third those in cattle. Although the elimination half-life after SC and IV administration of ivermectin is of similar duration, slow absorption from the injection site may broaden the concentration-time profile, with Cmax in peripheral plasma of cattle occurring as late as 96 hr. The Cmax and AUC in pigs and goats are considerably lower than those in cattle, horses, and sheep. Pigs, and possibly goats, may metabolize ivermectin faster than other species.
In ruminants, the macrocyclic lactones are, like benzimidazoles, most effective if deposited directly into the rumen. A 3- to 4-fold decrease in Cmax and AUC of ivermectin after intra-abomasal compared with intraruminal administration has been reported. Significantly, time to maximal concentration of ivermectin was reduced from 23 hr to 4 hr with the former route of delivery.
Concentrations of ivermectin are high in digesta sampled from the distal intestine, indicating that biliary secretion is an important pathway for clearance of macrocyclic lactones. This pathway also has been conclusively demonstrated for clearance of benzimidazole compounds. The extended high concentration in bile is influenced by prolonged exchange of drug from lipid reserves and the enterohepatic recycling of biliary compounds through the portal and biliary pools. The macrocyclic lactones are primarily excreted in the feces, the remainder (<10%) in the urine. The more lipophilic macrocyclic lactones are also excreted in milk.
Secretion via the liver and bile is especially important for drugs active against adult Fasciola spp. The fasciolicidal effects of salicylanilides (such as rafoxanide) in sheep depend on persistence of the drug in plasma, which influences their transport throughout the body and rate of elimination. Closantel, rafoxanide, and oxyclozanide have long terminal half-lives in sheep (14.5, 16.6, and 6.4 days, respectively), which are related to the high plasma-protein binding (>99%) of these three drugs. Residues in liver are detectable for weeks after administration. Associated with persistence, however, is the need for longer withholding periods. Oxyclozanide also is bound to plasma protein and then metabolized in the liver to the anthelmintically active glucuronide and excreted in high concentration in the bile duct, where it encounters the mature flukes.
Immature flukes in the liver parenchyma ingest mainly liver cells, which contain little anthelmintic; plasma-protein binding limits entry of the drug into the tissue cells. As the flukes grow and migrate through the liver, they cause extensive hemorrhaging and come into contact with anthelmintic bound to plasma protein. When they reach the bile ducts, they are in the main excretory channels for the active metabolites of the fasciolicides and are exposed to toxic concentrations. This may explain why mature flukes are more vulnerable to most fasciolicides than immature ones. The higher concentrations of fasciolicides and their metabolites in feces than in urine suggest that the bile ducts are their main excretory pathways.
It is important to understand the pharmacokinetics of prescribed anthelmintics. For example, nitroxynil has good efficacy against F hepatica in cattle and sheep and against H contortus, but because rumen bacteria metabolize and destroy the activity of nitroxynil, it must be injected.
After PO administration, monepantel is quickly absorbed into the bloodstream and metabolized to a major extent within 4 hr into monepantel sulfone. The sulfone expresses in vitro anthelmintic activity similar to that of the parent molecule and is responsible for the anthelmintic effect in animals, because 95 % of the administered dose is metabolized into the sulfone. The Cmax of monepantel sulfone was 4 fold-higher compared with that measured for the parent compound. After PO administration in sheep of the recommended dosage of 2.5 mg/kg, the elimination half-life of the sulfone metabolite in plasma was 48.7 hr, with a mean residence time of 79.3 hr. Approximately 27% of the administered dose is excreted through the feces in the form of the sulfone derivative. The remaining amount is further metabolized and partly excreted through urine (up to 30% of the administered dose). In addition to the sulfone, the parent monepantel contributes to the anthelmintic activity against abomasal nematodes, because the concentration of the parent monepantel is considerably higher in the abomasum than in plasma.
Studies in rats have been done to assess the general distribution, metabolism, and excretion patterns of emodepside after PO and IV administration. Bioavailability after PO administration is ~50%. Emodepside is distributed throughout the whole organism, but highest concentrations are found in fat tissues, where it forms a deposit that is slowly released. Emodepside is excreted predominantly via the bile and then eliminated in the feces. Approximately half of the administered dose is excreted within the first 24 hr. The elimination half-life after both PO and IV administration is 39–51 hr. Approximately 45%–56% of the administered dose is excreted unchanged, the rest in the form of inactive metabolites. After topical administration in cats, emodepside is absorbed slowly into the bloodstream. Maximum plasma levels are reached 2–3 days after treatment. Absorption after PO administration in dogs is higher if administered to fed animals.
Pharmacokinetics demonstrate that after a single oral administration, maximum concentrations of derquantel were reached at 4.2 hr. The terminal half-life of derquantel was 9.3 hr, and the absolute bioavailability was 56.3%. Metabolism of derquantel is extensive and complex. Derquantel undergoes biotransformation to a large number of metabolites over a short time and, as a result, extensive variation in metabolites has been found in tissues and over time periods.
Praziquantel is rapidly and almost completely absorbed from the GI tract. After absorption, praziquantel is distributed to all organs; it is believed to re-enter the intestinal lumen via the mucosa and bile in dogs. Praziquantel is rapidly hydroxylated into inactive forms in the liver and secreted in bile. It has a wide safety margin.