Acidic drugs, oral absorption

Drug In vitro Clinical Pharmacology Effect on Gastric Acid Secretion Oral Absorption Plasma Half-life (h) Volume of Distribution (Lkg b Plasma Protein Binding Excretion Metabolism... 

May cause mild CNS and GI effects and 1 bioavailability of drugs that require acidity for oral absorption (e.g., fluoroquinolones, ketoconazole). Inhibit P450 — >L elimination of diazepam, phenytoin, and warfarin. 

Acidic molecule oral absorption 1 by drugs including bile add sequestrants. 

Both influx and efflux transporters are located in intestinal epithelial cells and can either increase or decrease oral absorption. Influx transporters such as human peptide transporter 1 (hPEPTl), apical sodium bile acid transporter (ASBT), and nucleoside transporters actively transport drugs that mimic their native substrates across the epithelial cell, whereas efflux transporters such as P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) actively pump absorbed drugs back into the intestinal lumen. 

True zwitterionic compounds are rare among drugs. The oral absorption of truly zwitterionic compounds is poor unless the compound is a substrate for an absorptive biological transporter as in an a-amino acid which is a substrate for the PepTl nutrient transporter. The aqueous solubility of a true zwitterionic compound will be at a minimum at the isoelectric point which unfortunately for many compounds happens close to the neutral pH at which oral absorphon occurs. Species extrapolation predicting oral absorphon and pk/pD from preclinical animal tests to man are difficult for zwitterions. 

Vitamin B12 generally is well tolerated and exhibits minimal adverse effects. Injection-site pain, pruritus, rash, and diarrhea have been reported. Drug interactions have been observed with omeprazole and ascorbic acid that decrease oral absorption. 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

Oral absorption of drugs is influenced by gastric acidity and emptying time. Gastric acid is rarely found in the... 

It is orally effective broad spectrum imidazole antifungal drug. It is useful in both dermatophytosis and deep mycosis. Oral absorption is facilitated by gastric acidity. It is highly protein bound, metabolised in liver and metabolites are excreted in urine and faeces. Its spectrum is similar to that of miconazole and is more active against Coccidioides. 

Due to first-pass metabolism, if administered alone lopinavir has varied plasma levels. This problem is overcome by adding ritonavir to the formulation. Its oral absorption is rapid, and its bioavailability is increased by food rich in fat content. Lopinavir is metabolized by cytochrome P-450 isoenzyme CYP3A4. Most of the drug in the plasma is bound to ai-acid glycoprotein. In combination with other antiretroviral agents, lopinavir is indicated for the treatment of HIV infection. 

The oral absorption of amprenavir is rapid, and peak concentrations are reached between 1 and 2h administration of both amprenavir and fosamprenavir with food is not a concern. Fosamprenavir is dephosphorylated to amprenavir in intestinal mucosa. Amprenavir is 90% bound to plasma protein with most to ai-acid glycoprotein. It is metabolized by the cytochrome P-450 system, CYP3A4, in the liver, and more than 90% of the drug is excreted after its metabolism in feces. In combination with other antiretroviral agents, amprenavir/fosamprenavir are indicated for the treatment of HIV infection. 

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47 Antimycobacterial Drugs). Clarithromycin also has activity againstM leprae and Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin. 

To account for the good oral activity of enalapril, attention was drawn to the fact that enalaprilat is an anionic zwitterion at physiological pH (pffa s 2.8, 3.5 and 7.6), whereas only the carboxyl of enalapril is ionized (pKa s 3.0 and 5.4) (118,120). The possibility was considered that enalapril is absorbed from the intestine, as are bile acids and other carboxyl-containing compounds including the nonsteroid anti-inflammatory drugs. Later, Amidon and colleagues published data supporting peptide transport in the oral absorption of enalapril (126,127). 

---