This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol. Pharmacokinetics
After being taken by mouth, paracetamol is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same. In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate, but not high protein or high fat, food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.Paracetamols bioavailability is dose-dependent: it increases from 63% for 500 mg dose to 89% for 1000 mg dose. Its plasma terminal elimination half-life is 1.9–2.5 hours, and volume of distribution is roughly 50 L. Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21%. The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L). After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L). Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5% of the drug are excreted unchanged in the urine.
These kinases are present in 10-fold greater concentrations in CMV or herpes simplex virus (HSV)-infected cells compared to uninfected human cells, allowing ganciclovir triphosphate to concentrate in infected cells.Ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate (dGTP). It is incorporated into viral DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases. Ganciclovir triphosphate serves as a poor substrate for chain elongation. Once incorporated into viral DNA due to its structure similarity to dGTP, chain termination occurs once a single nucleotide is added to the distal hydroxyl group of the incomplete deoxyribose ring of ganciclovir. Pharmacokinetics
Oral bioavailability is approximately 60%. Fatty foods significantly increase the bioavailability and the peak level in the serum. It takes about 2 hours to reach maximum concentrations in the serum. Valganciclovir is eliminated as ganciclovir in the urine, with a half-life of about 4 hours in people with normal kidney function. The mechanism of this drug is activation via a viral protein kinase HCMV UL97 and subsequent phosphorylation by cellular kinases. The phosphotransferase enzyme can likewise activate valganciclovir. Chemistry
The synthesis of valganciclovir has been reviewed. Many routes use ganciclovir as a starting material. Society and culture
Price and patent status
Roches Valcyte is protected by patent. However a generic version manufactured by Japanese-owned Indian company Daiichi-Ranbaxy was found by the District Court of New Jersey, USA not to infringe Roches patent. In November 2014, FDA approved generics by two manufacturers.The price of a four-month course of valganciclovir from Roche is about US$8,500 in high-income countries, $6,000 in India.