Oral doses

PROBLEM If a drug has 100% oral bioavailability, will an IV bolus and oral dose of the same size have the same Cpmax Use the parameters of the drug in the previous Sample Calculation (except F = 100%) to prove that the answer is no. 

SOLUTION First we need to know the parameters of the previous drug. They were Vd = 70 L, kab = 0.8 IT1, and kei = 0.3 IT1. Using the same previous dose of 500 mg, we can quickly calculate Cpmax for the IV bolus (same as Cp°) with a rearranged Equation 7.13. 

Cpmax for the oral dose occurs at tmax, which we can calculate with Equation 7.30. 

Cpmax for the IV bolus is 7.1 mg/L, while the oral dose only reaches 3.8 mg/L. The answer is no. Even with 100% oral bioavailability, an oral dose does not achieve the same Cpmax as an IV bolus. This statement is true for all oral drugs. 

Despite its popularity, oral delivery would be worthless if it were unable to sustain consistent Cp levels over time. When spaced properly with a correct dose, orally delivered drugs can 

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I6I C. Warfarin baits need contain only 0 025% active principle, and rats are killed after ingesting about 5 doses the bait can be left down and the risk of acute toxicity to man or domestic animals is not serious. In common with other coumarin derivatives, warfarin reduces the clotting power of blood and death is caused by haemorrhages initiated by any slight injury. Warfarin is a vitamin K antagonist, and large oral doses of the vitamin can be given as an antidote. 

The cured 2-cyanoacryhc ester polymers are relatively nontoxic. Oral doses of 6400 mg/kg failed to kill laboratory rats. Mild skin irritation was observed with guinea pigs, but there was no evidence of sensitization or absorption through the skin (15). 

Dietary Copper. Analytical data indicate that many diets contain less than the RDA for copper (109). Excessive copper has been reported to be fatal for oral dose levels of copper sulfate of 200 mg/kg body weight for a child and 50 mg/kg for adults. 

Poly(tetramethylene ether) glycols were found to have low oral toxicity in animal tests. The approximate lethal oral dose, LD q, for Terathane 1000 has been found to be greater than 11,000 mg/kg (272). No adverse effects on inhalation have been observed. The polymer glycols are mild skin and eye irritants, and contact with skin, eyes, and clothing should be avoided. Goggles and gloves are recommended. In case of contact with the skin, wash thoroughly with water and soap. If swallowed, no specific intervention is indicated, because the compounds are not hazardous. However, a physician should be consulted (260). 

Finally, in another study related to nutrition and the immune response in the aged, old mice were given oral doses of two amino acids (qv), lysine and arginine. The treated mice showed evidences of recovered mitogenic responsiveness, expression of T-ceU markers, and production of thymic semm factor (thymulin). The effect of the amino acid combination, sold commercially as Neoiodarsolo, seems to consist mainly of the reactivation of the... 

The development of easy-to-use assays for determining theophylline blood levels afforded a handle on maintenance of effective but nontoxic levels. The relatively good availabihty of such assays in the United States probably contributed to the historical preference for theophylline treatment by U.S. physicians. Careful titration of the dose must be done on a patient-by-patient basis because individual rates of metaboHsm vary widely. Most ( 85%) of an oral dose of theophylline is metabolized by Hver microsomal enzymes. As a result many dmgs, eg, cimetidine [51481-61-9], anticonvulsants, or conditions, eg, fever, cigarette smoking, Hver disease, which affect Hver function alter theophylline blood levels. 

Up to 80% of oral doses of ascorbic acid are absorbed in humans with intakes of less than 0.2 g of vitamin C. Absorption of pharmacological doses ranging from 0.2 g to 12 g results in an inverse relationship, with less than 20% absorption at the higher doses. A single oral dose of 3 g has been reported to approach the absorptive capacity (tissue saturation) of the human intestine. Higher blood levels can be attained by providing multiple divided vitamin C doses per day. 

Systemic reactions are less severe than with diethylcarbama2ine. The most commonly seen reactions are fever, rash, and lymph-node pain or swelling. Suppressive ivermectin therapy consists of a single oral dose every 6—18 months. The required duration of suppressive therapy is unknown, probably at least three years (36). Ivermectin is available from the CDC Dmg Service on request. It is manufactured by Merck Sharp and Dohme in the United States and England. 

Potassium Iodide. When potassium iodide [7681-11-0] is adrninistered orally for several (6—8) weeks, a therapeutic effect may be obtained ia the subcutaneous form of sporotrichosis. Amphotericin B is used iatravenously to treat systemic sporotrichosis. The KI dosage is usually a saturated solution ia water (1 g/mL). The usual oral dose is 30 mg/kg/d. Children should receive five droplets, three times a day (after meals) the dose may be iacreased to 15—20 droplets. Side effects iaclude digestive disorders, swelling of the saUvary glands, and lacrimation. Thyroid function tests may be disturbed. 

The activity of ivermectin against the filarial parasite Dirofilaria immitis in dogs suggested a possible role for the control of filarial parasites of humans (20). It has been extensively tested in human onchocerciasis and is now considered to be the dmg of choice. In a single yearly oral dose, it suppresses microfilariae in the skin and eyes and, in most cases, prevents the progression of the disease to blindness. Table 4 shows the results of a 30-patient double-blind study recorded over one year. 

Ten patients received a single oral dose of ivermectin, 12 mg. 

Two forms of lymphatic filariasis are found in India. The Bancroftian form is the most common and accounts for more than 90% of the disease whereas Bmgian filariasis accounts for the rest. In a study carried out in India (6) in 40 patients with Wuchereria Bancwfti filariasis treated with single oral doses, all of the dose levels chosen (25, 50, 100, and 200 mg/kg) were efficacious in clearing microfilariae from the blood of all patients treated. However, after three months some microfilaria recurred in the blood of most patients (Table 5). Further studies are planned and some are underway using different doses and regimens. Ivermectin still appears to hold promise as a new treatment for lymphatic filariasis. 

Inhalation of 3,000 ppm benzene can be tolerated for 0.5—1 h 7,500 ppm causes toxic effects in 0.5—1 h and 20,000 ppm is fatal in 5—10 min (123). The lethal oral dose for an adult is approximately 15 mL (124). Repeated skin contact is reported to cause drying, defatting, dermatitis, and the risk of secondary infection if fissuring occurs. 

Nicorandil. Nicorandil is a potassium channel opener that can lower blood pressure 21, 20, and 29 mm Hg after single oral doses of 10, 20, and 30 mg, respectively (250). There are no significant changes ia heart rate. Headache is the primary side effect. Nicorandil has potent coronary vasodilator effects. It causes sustained vasodilation of arteriolar resistance and venous capacitance blood vessels, thus reduciag cardiac preload and aftedoad. 

Cromakalim. Cromakalim has along half-life (254). Cromakalim at an oral dose of 1.5 mg ia humans significantly lowers blood pressure 19/12 mm Hg (systohc/diastoHc pressure). It iacreases reaal blood flow, PRA, and heart rate. Cromakalim has bronchodilating activity that is beneficial for hypertensive asthmatic patients. Because of some undesirable effects seen ia cardiac papillary muscles of animals oa long-term treatmeat, future clinical trials are to be carried out usiag the active enantiomer, lemakalim (BRL 38227). 

Humans tolerate fairly large oral doses of copper without harmful effects, and it is used in various therapies (66). Copper sulfate is a powerful emetic and has been used clinically in the treatment of intoxications. 

Contact or ingestion of cyanamide must be avoided, and precautions taken to prevent inhalation of dust or spray mist. In rat studies cyanamide-100 toxicity ranges from a single oral dose LD q of 280 mg/kg to a single dermal dose LD q of 590 (420—820) mg/kg. The compound is, therefore, considered to be moderately toxic both by ingestion in single doses and by single-skin appHcations. An aqueous paste of the product is corrosive to rabbit skin. Small quantities of the dry product produced severe irritation when introduced into the conjunctival sac of the rabbit eye. 

Animal acute oral LD q, g/kg Toxicity rating Probable lethal oral dose for 70 kg person, g ... 

Codeine, like morphine, is isolated from the opium poppy. However, the low yield of 0.7—2.5% does not provide sufficient material to meet commercial demands. The majority of marketed codeine is prepared by methylating the phenolic hydroxyl group of morphine. Morphine yields from opium poppy are 4—21%. When prescribed for cough, the usual oral dose is 10—20 mg, three to four times daily. At these doses, adverse side effects are very few. Although the abuse potential for codeine is relatively low, the compound can substitute for morphine in addicts (47). 

Toxicity rating Commonly used term LDso Single oral dose for rats (g/kg) 4hr Vapour exposure causing 2 to 4 deaths in 6-rat group (ppm) LDso Skin for rabbits (g/kg) Probable lethal dose for humans... 

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